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# David Ho

David Ho

### Director, Aaron Diamond AIDS Research Center

By David Zierler, Director of the Caltech Heritage Project

January 10, 18, February 1, 7, 15, and March 8, 2022

DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Monday, January 10th, 2022. It is my great honor and privilege to be here with Dr. David D. Ho. David, it's great to see you. Thank you for joining me today.

DAVID HO: Good to see you, David. It's my pleasure. I'd do anything for Caltech.

ZIERLER: That's great. To start, and I know this will be a complicated answer, would you tell me your titles and institutional affiliations?

HO: Yes. I'm the Founding Scientific Director for the Aaron Diamond AIDS Research Center, and I am a Professor of Medicine and Microbiology & Immunology at Columbia University Medical Center.

ZIERLER: You are named in honor of Clyde and Helen Wu. I wonder if you could talk a little bit about the Wus, and if they have any particular connection to your research.

HO: Clyde was an alum of Columbia and was a board member for the university for a long, long time. He's also a very generous philanthropist and endowed a number of professorships here, and I occupy one of those chairs. They also support many other programs at Columbia. Clyde unfortunately has passed away.

ZIERLER: Tell me a little bit about Aaron Diamond and the motivation to start the AIDS Research Center.

HO: Aaron Diamond was a Harvard Business School graduate, a real estate developer in New York City, who made quite a fortune in that business. I think toward the end of his life, he and his wife, Irene Diamond, started to form a foundation called the Aaron Diamond Foundation, and to give back to New York City in particular. They concentrated in a few areas—medical research; arts, particularly Lincoln Center, Juilliard; and then the third aspect was human rights. They formed the Foundation in the early 1980s as the AIDS pandemic was brewing, and they thought that New York City, being the epicenter in the U.S., was doing too little, and they opted to invest their money to set up a new institute, here in New York City, devoted to AIDS research. I was recruited to be the founding director.

ZIERLER: Just a snapshot in time—January 2022—what are you working on currently?

HO: Currently, we've been focused almost exclusively on the COVID-19 pandemic, and we've been doing that since January of 2020, so about two years. Ever since China locked down the city of Wuhan, we knew this was a big problem, and we thought as virologists we should help address the burgeoning outbreak. Then it turned into a pandemic of enormous proportions that I certainly did not expect.

ZIERLER: You wear so many hats. I wonder what title or scientific discipline you might consider as an umbrella term that relates to all of the scientific and medical research that you've been involved in. Microbiology, immunology, virology, of course you're a medical doctor, you're a scientist. What's the term that you would say fits most widely everything that you've been involved in?

HO: I like two particular terms. One is physician-scientist. I'm trained as a physician, but I focus on medical problems in the lab. The other is medical virologist. Throughout my career, I have focused largely on HIV, but to some extent on coronaviruses, influenza viruses, and Ebola. I would say to date, with the exception of the last two years, AIDS research was predominant.

ZIERLER: In reflecting on all of your career, because you're an MD but you've been involved in so much fundamental science, when for you is it about the basic science, just understanding how nature works, and when is it specifically focusing on translational or clinical applications of that basic knowledge?

HO: I went to medical school not to become a practicing physician. I wanted to solve medical mysteries. That's why I went to medical school. I think that was framed by the Caltech experience as an undergraduate. But I did train as a physician, as an internist, infectious disease specialist. I combined that curiosity in science with my medical background. The intersection is obviously infectious diseases that require a lot of bench research. As I was finishing my medical training, AIDS emerged. That was a big medical mystery at the time, and therefore I focused on that, and did so until the last couple of years.

ZIERLER: What have you been able to achieve, either by your training or the kinds of questions that you've posed, by going to medical school as opposed to pursuing a PhD, for example, in microbiology or immunology?

HO: I think my lab experience, even though I don't have a PhD, is pretty much comparable to those who have a formal PhD degree. The MD degree, but more importantly the clinical training, gave me a perspective that is very helpful in guiding my research directions. It makes me appreciate the fundamental problems from a patient angle, a physician angle, that is probably different from the typical PhD basic scientist. Given my background, I have operated at the interface between basic science and translational medicine. That is a pretty rich space for investigation. That's what I did in AIDS research. That's what I'm doing now, with the COVID-19 pandemic.

ZIERLER: In your capacity as a mentor to students, is the career path that you took what you would recommend to students who have similar interests and ambitions?

HO: I think it's the career path for a small number of people. A lot of people who go to medical school want to practice medicine and take care of patients, and that's very appropriate. But for those with a scientific bent and a curious mind, I think the career path I took is really exemplary. If they want to solve the unknowns in the medical profession, I think being a physician-scientist is a great way to go about doing that.

ZIERLER: I'd like to ask a question that will combine so many different aspects of your career. I'll ask you to think about your initial reaction to two of the major events that have defined your research. If you can think back, if you have a clear memory of realizing that there was this problem that would go on to be the HIV pandemic, and then compare that much more recently to this global problem that originated in Wuhan that came to be known as SARS-CoV-2, the COVID-19 pandemic. Can you remember your initial reaction when you realized that these were both major problems, and compare and contrast those reactions?

HO: Yes. For the early days of HIV/AIDS, fortuitously I saw some of the earliest cases, on the Westside of Los Angeles, as a medical resident finishing training. At that time, it was a curiosity, rather esoteric, certainly with the first case, and then even with the few ensuing cases. They were a medical curiosity, unexplained. But those cases caught my interest, and I could tell you that what caught my interest was the fundamental problem of how you could have a disease that's transmitted from one person to another that destroyed the immune system. You would not find such description in the textbooks. So it was kind of apparent even to a young physician, young scientist like myself, that we were confronting a new problem. But at that early stage, it was just a medical mystery, certainly not a pandemic, not even an epidemic. But if you then look at what happened in 1981, 1982—initially it was gay men, and then there were some Haitians, and then there were blood transfusion recipients, hemophiliacs, and so it kind of grew slowly over months. Then a year or two later, I think people began to realize this was much bigger. Clinically speaking and from a public health perspective, it was much bigger than we had appreciated. It was a gradual realization that this was a disease of great medical importance and great public health importance. That was slow-evolving.

The current COVID-19 pandemic is very, very different. Things move at such a fast pace. Also, you have to bear in mind, this coronavirus had two previous outbreaks of note. There was SARS in 2002, 2003, and there was MERS that came about nine, ten years ago, from the Middle East. Now, both were outbreaks. Of course SARS was about 8,000 cases and 800 deaths. MERS was smaller in number but higher mortality. The field kind of recognized that such coronaviruses could be problematic. But at as soon as SARS-CoV-2 was detected in China in late December, and sequence published in early January, and the fact that it was spreading so rapidly in Wuhan to lead the Chinese government to lock it down, we knew that it was much more transmissible than other coronaviruses. Therefore, once it already was so extensively spread in Wuhan, you knew cases have gotten out of Wuhan and probably not only to China but also the rest of the world. Indeed, that's what happened, and the rest is history. So for the COVID-19 situation, it just transpired so quickly. Everything that we had to do is at warp speed in order to respond, in order to chase after this rapidly spreading virus.

ZIERLER: I'll ask you a question that will combine a bit of Virology 101 and also ask you to reflect on the role of politics and business in public health decision-making. As so many people are wondering, why has the development of a vaccine for HIV remained elusive 40 years-plus, and we see this remarkable miracle of the development of a tremendously successful vaccine for SARS-CoV-2?

HO: That's a great question. It's not because of lack of effort or funding or talent devoted to development of an AIDS vaccine. That has been the holy grail in the field for a long time, but without any real success. I would dare say even with the activities going on, we're not going to have a vaccine for HIV/AIDS anytime soon. But that work on the HIV vaccine actually helped facilitate the development of the COVID-19 vaccine, because a lot of the technology—the HIV vaccine is so difficult, due to the fundamental properties of the HIV envelope protein that sits on the surface of the viral particle. It has a shield. It has great mutations. It has just been really difficult to elicit strong antibodies that could kill HIV.

SARS-CoV-2 is fundamentally different. That protein, although it's changing, as we have witnessed over the past year with the development of many, many variants, it doesn't have the same extent of mutations as HIV. It also doesn't have the shield that HIV has. A lot of the technologies that have been used to develop HIV vaccine were quickly applied to SARS-CoV-2, and of course we know how successful it has been in vaccines. Particularly the so-called mRNA vaccines have been extremely protective on the short term. Of course we're learning that the protection wanes with time, and protection is lost against certain variants. But it has been night-and-day difference—40-plus years for an HIV vaccine without success, and something like six to nine months, we had multiple vaccines for SARS-CoV-2.

ZIERLER: On the concept of global inequity and its influence on scientific research—of course in the developed world, thank goodness an AIDS diagnosis, or an HIV diagnosis, is no longer in large scale a death sentence. But in the developing world, HIV still does kill many thousands of people a year. To be clear, if we didn't have the retroviral technology, and that AIDS was as deadly today as it was in the 1980s and 1990s, would there be more resources put into an HIV vaccine?

HO: Actually, a tremendous amount of resources have been devoted to HIV vaccine research, particularly from the NIH and from the Gates Foundation and from the Wellcome Trust, so I wouldn't attribute the lack of a vaccine to the lack of funding, related to what I mentioned when you asked the previous question. I think the fact we don't have a vaccine is due to the properties of HIV. In terms of global inequities, I think early on, the life-saving medicines that American patients took were not available in, say, sub-Saharan Africa. But over time, due to a number of initiatives taken by the U.S. government, by various foundations, more and more of these drugs have been made available for the developing world. As we speak, I think about 25 million people in poorer countries are now on medications. These, granted, are largely generic medications, but nonetheless, they do work and help to control the virus. Therefore, mortality has really declined. Of course, there's still a large segment of the developing world with HIV infection that has not received these life-saving medications, so more work needs to be done. But $10,000 a year in medication in the U.S. now could be administered for a few hundred dollars a year abroad, using generics, and that has really made a huge difference. For the HIV epidemic, just to use rough numbers, 70 million have been infected; about half have died, and half are living with the virus. That half would die, if untreated, over an eight- to ten-year period. So, a lot of people are living fairly normal lives with fairly normal life expectancy on such medications now. ZIERLER: To transfer the concept of global inequity as we understand how COVID-19 continues its devastation, I wonder if we can take a step back and reflect on the importance of having a vaccine that was readily available to the entire world. Isn't one of the lessons of omicron that as long as being fully vaccinated and boosted is essentially a luxury of the developed world, won't the COVID-19 virus simply continue mutating until we're all at risk? HO: I think the global inequity is very, very apparent here, during the COVID-19 pandemic. The best vaccines are the mRNA vaccines, and they're the least available to the developing world. The developing world have largely gotten the Chinese vaccines, their so-called killed-virus vaccines, and to some extent the AstraZeneca and the Russian vaccines. Those are so-called viral vector vaccines. We know from lots of experimental and clinical data that they don't work as well, and therefore they don't protect as well, yet much of the developing world has either gotten nothing, or gotten one of the inferior vaccines, and they're not going to be very well protected. Whereas in the U.S., Europe, Japan, a large segment of the population have gotten the best mRNA vaccines, and quite a number of people are triply vaccinated and therefore pretty well protected. So the virus I suspect will continue to circulate. Right now, the omicron variant is hitting everybody, but SARS-CoV-2 will continue to be devastating to the developing world unless the vaccination rates go up, and go up with better vaccines. ZIERLER: I wonder if you can explain why the mRNA vaccines are so much better than what Russia and China have produced. HO: There are many technical reasons. It's just that could you show the immune system the so-called spike protein of SARS-CoV-2, and show it in great abundance, and with the correct conformation. The mRNA vaccines express at high levels and therefore the abundance is there, and they are designed to show the spike in stable form. In contrast, if you take the Chinese vaccines or the AstraZeneca vaccines, they grow the virus up, but the spike is not in great abundance, and some of the spikes have fallen apart. Therefore, they are not as good in raising a robust antibody response against the spike, and therefore the antibody levels are lower, and particularly those antibodies that could kill the virus, which we call neutralizing antibodies, are particularly low, and therefore confer less protection. ZIERLER: I wonder, then, if the obvious solution is simply to distribute mRNA vaccines worldwide. What's standing between that matter of first of all American national interest, if we ever want to move beyond this, and actually achieving that result? HO: Right now there are only two companies, Pfizer working together with BioNTech, and Moderna. Moderna is, relatively speaking, a small company, so their manufacturing capacity has been limited. Pfizer has done a better job, because it's a big player in the field, but that's all we've got. To crank out the doses requires time. I think they're doing so. They will continue to scale up, and much of the world, I think, deserves to receive the best vaccines, but that's not the case so far. It has to do with limitations in manufacturing. Also, to be frank, they want to make a good profit, and the paying market is in the rich countries. If you want to charge the kind of prices they're charging now to much of Africa, that's simply not feasible. Somebody has to end up paying that bill, or the companies would have to markedly reduce their costs. ZIERLER: Asking you strictly in your own personal capacity, do you think that the right move would be something akin to nationalizing these companies and taking away the intellectual property so that a generic version can be distributed much more quickly and produced worldwide? HO: I think we need to reach terms like what we did for AIDS treatment. I think the companies should be allowed to make their profit and to regain their research dollars in the developed countries. But they could, and should, make these vaccines available essentially at cost, or turn the IP over to allow local manufacturers to produce them. Now, that's easy to say, but the technology is fairly new, so even if you turn it over to Brazil or Africa or even China, it's not clear that they could get going anytime soon. There are lots of economic and technical reasons why the inequity continues. ZIERLER: Turning locally, what does the situation look like in New York right now, as it is struggling to deal with omicron? HO: The surge is incredible. New York could record upwards of 50,000 cases a day. That, in terms of case numbers, is something we never witnessed before, and the surge is larger than any of the previous waves. Fortunately, omicron is not as virulent as previous variants, and therefore, as of today, the hospitalization and ICU admissions have not reached a peak yet, but we all fear that given another few weeks—we know those are lagging indicators, and given another few weeks, the hospitals will be overwhelmed, and at the same time, staffing is an issue because so many healthcare workers are also infected, just like the rest of the population, so we have a shortage of manpower right now. The burden on the healthcare system is tremendous right now, not just in New York but everywhere. New York, as usual, is hit first by this omicron wave, and now we're beginning to see it in the rest of the country. In New York, vaccination rates are high, included those who have received boosts. As you know, many parts of the country have much lower vaccination rates, and they're going to be hit much harder. That peak, for New York, is expected probably in a week or two, and the rest of the country, probably one or two weeks after that, so the worst is yet to be seen. ZIERLER: What do you attribute into what can only be understood as a massive public health failure, in messaging, in trust-building, when we look at the fact that really only 60% or thereabouts of Americans are fully vaccinated, when this of course is free and available to everybody? HO: Obviously the government could have done a better job with year one of the pandemic. The government under Trump in particular trivialized the pandemic and thought it was going to go away and misled much of the public. The CDC was ill-prepared with tests, and so there was not enough testing. There was not enough PPE. Masks and sanitizers and other things were in shortage. Logistically, the country did a poor job. But fundamentally, the scientific community I think responded well, and the biotech and pharmaceutical industry responded well. People recognized how big a problem this was. Our society was turned upside down. In short order, a number of therapies were developed, and a number of vaccines were developed, in record speed. That's a great accomplishment. But I think the root of your question is really focused on why we are doing so poorly with effective vaccines. Unfortunately, we not only have a rapidly spreading virus; we also are facing rapidly spreading false information. We really have a huge problem with that. Something like a third of our population question whether this is a real pandemic. They question whether vaccines really work. There's so much misinformation about vaccine side effects that are absolutely false. There's so much false information about masks. It's hard for people to know what the truth is. America, in particular, along with some of the Western European countries, value freedom so much, personal freedom. I value freedom, and I respect that, but freedom should come with responsibility. A lot of that second component is forgotten. Total freedom without social responsibility is what's driving much of the pandemic, for the last two years, and now the omicron wave. It's so bad, and yet people still question vaccines, question masks, and value their "I want to be able to do whatever I want" with total disregard for the public good. That is the tragedy we face today, and I don't know what to do about it. The Biden administration is doing everything they could to get the message out, but there's a segment of society that's pushing a totally different message. ZIERLER: There's the carrot approach, and of course there's the stick approach. As a medical doctor bound by the Hippocratic oath, and someone who well appreciates the importance of health insurance and paying insurance premiums, given the fact that so much of the country is less vaccinated than New York, and if we can extrapolate really to a scary situation where much of our healthcare infrastructure is in danger of collapsing, is one way to encourage more people to get vaccinated to put out messages saying, "If you don't want to take the vaccine, that's fine, but then don't come to the hospital"? Or, "If you don't take the vaccine, any healthcare that you get, you have to pay for out of pocket." Do you think we'll get to the point where we'll need to force this upon people so that they take the message or assume the responsibility? HO: I think society as a whole has utilized both approaches, the carrot and the stick. New York City, they were giving$100 away for vaccination, or giving away subway tickets, or Metro North tickets so people could get vaccinated. That's the carrot. The stick—there's a vaccine mandate for restaurants, for public gatherings. If you cannot show that you're vaccinated, or now boosted, you cannot attend a basketball game at Madison Square Garden, for example. Many, many employers have mandated vaccines. If you don't wear a seatbelt and the police catch you, you pay a fine, right? If you choose not to take a vaccine, as you indicated, you may face a higher insurance premium, for example. That's the penalty. That's because your risk of being really sick and hospitalized and going to the ICU is so much higher if you're unvaccinated than if you are vaccinated. It's going to come to a lot of these solutions using both carrot and stick approaches.

ZIERLER: Of course omicron might take us down an optimistic path or a pessimistic path. Let's start with the optimism first. What do you think are the prospects, given the fact that omicron is slightly less virulent, that it does not manifest in the lungs, to what extent does that tell us that SARS-CoV-2 is evolving to become more of an endemic type flu, and that this is something that we'll have to get inoculated on an annual basis just like influenza, and that's going to be over the long term how we achieve some kind of a path back to normalcy? On the other hand, to what extent does the vaccine evasiveness of omicron just suggest that, as long as the world remains largely unvaccinated, this thing will continue to mutate to the point at which we're in a situation where it's as dangerous as it was in early 2020?

HO: I think we're fortunate that omicron is not more virulent, not infecting the low respiratory tract as well as the upper respiratory tract. There are a lot of things we still don't understand, so we should not be jumping to conclusions. But the optimistic view is that it's less virulent, and yet it's so transmissible that it's pretty much going to infect not only the vaccinated, but also the unvaccinated. The level of immunity in the population is going to go way up, so it's going to serve as a vaccine. In virology terminology, we would call it a live attenuated virus vaccine. Of course, as it rips through the population, it's going to cause a lot of casualties, because of the sheer number of people infected, but the optimistic view is down the line, this would be better for the population, because the level of general immunity will be so much higher. For those who were vaccinated, they would get another boost from omicron infection. For those who were unvaccinated, omicron, if they manage to overcome the infection, they will develop sufficient immunity to protect against subsequent infections. So the optimistic view would be that on the short term, we would suffer, as we are experiencing, but in the long term, it could possibly bring a faster end to the pandemic and turn it into something that's more endemic, brewing at low level throughout the population.

But let's keep in mind that omicron is only one variant, and how these variants appear so far is seemingly stochastic. It happened. Who knew? Delta was so dominant, and so we expected the next variant to be emerging from delta, but omicron did not emerge from delta. Omicron emerged somewhere in Africa, quietly, from a variant called B.1.1. which was at low level, was not on anyone's radar, and in the course of a month, it just appeared and spread so rapidly. So something unexpected could still come, and what if it's omicron 2, with virulence? That would be terrible. The scientists and others have been wrong trying to guess the trajectory of SARS-CoV-2, so we're very reluctant to guess where this might end.

ZIERLER: Let's turn to guessing where it began. From the beginning, did you have a strong sense of the so-called debate about zoonotic versus lab leak hypothesis? Have those views changed over time?

HO: No, my views are pretty much the same. This SARS-CoV-2 did not exist in anyone's lab. I'm a virologist. if I were a virologist in China who isolated this new novel virus, I would report it. That's what we do. Nothing that close to SARS-CoV-2 was ever identified and sequenced in a lab in China or anywhere else in the world. The closest viruses to SARS-CoV-2 are in bats, and they're largely bats in Southern China or Southeast Asia, so it's reasonable to assume that somehow the virus, the progenitor of SARS-CoV-2 emerged in a bat population with that virus that has yet been identified by anyone. How it got to Wuhan is a mystery. Those caves, bat caves are largely in Southwest China, or in places like Laos, Cambodia, Thailand.

What makes the lab leak theory a bit more attractive is the fact that Wuhan housed the BSL-4 lab that worked on these type of viruses and other viruses. But I think the most logical explanation is the Wuhan scientists at the so-called Wuhan Institute of Virology annually would make several trips to the bat caves to collect samples, to see if they could identify new viruses. To me, the zoonotic—if we want to explain why Wuhan, then I would say, well, could it be that it wasn't leaked from the lab, but one of the investigators brought it back? Initially, when a virus jumps into a new host, it's very inefficient. Over the last two years, we've seen how the virus gains traction in becoming more and more efficient in infecting humans, omicron being the ultimate example. So I would envision that sometime in 2019, maybe such a transmission occurred to the people who explored the bat caves. They may have mild symptoms and transmit, and it was very inefficient, sporadic, until one variant emerged in late November or December of 2019, and that began to take off. To me, that's the most plausible theory, but it's plausible, it's not proven. It's not discussed very much out there. People either think, "Well, it got into the animals at the market and then spread"—but why not other markets? Because Wuhan is one of many, many cities in China that would have such wet markets. This would explain why Wuhan, because Wuhan is the only city where the scientists sent folks to the bat caves on a regular basis.

ZIERLER: In that case, then, I wonder if you can explain, and perhaps this is more a cultural or a geopolitical question, if it is a zoonotic origin, why has the Chinese government not been more forthcoming about information that it has, and been more cooperative with, for example, the World Health Organization?

HO: I think you need to understand Chinese culture and the attitude of the Chinese Communist Party. There's no doubt that this pandemic emerged in China, so that's bad news, and you could say for the first few weeks, they handled it poorly and allowed it to turn into this global pandemic. The best time to put out a fire is turning from ember into a small fire, and that wasn't done, and this turned into an inferno. It's an embarrassment, and for the Chinese culture, you just don't talk about those negative things very much. They keep it a secret. Any type of bad news, they generally don't talk about very much publicly. It's a reflection of that. Then of course the Trump administration did not help, calling it "The China Virus"—

ZIERLER: "Kung Flu."

HO: "Kung Flu" and all sorts of other things, clearly trying to assign blame. I'm Chinese-American, and I'm probably more American than I am Chinese, but I do have a real appreciation for the Chinese culture. I would say, from my perspective, pandemics could emerge from anywhere. We should not get into the world of assigning blame to any particular country. Zika, the recent Zika, emerged from South America. Do we blame the South Americans? West Nile came from the Nile region. Do we blame the Egyptians? And in this case. In many other situations, we have had flu pandemics emerge from the U.S. or the Western world. We should not get into assigning blame, and China should not be overly embarrassed by the fact that this emerged from China. But that's their attitude. I don't think they're covering up a lab leak. I think they just don't want to share, and they also don't want to open their books to the rest of the world. That's sort of their general attitude.

ZIERLER: It's one problem from a public health perspective, of course, that China did not put out the fire in the early stage, if that was possible. It's quite another if the Chinese government continues to withhold info that would be valuable to ongoing COVID-19 research. Is that the case? Is there information that you feel that the Chinese government has that would be useful at this stage in the game?

HO: I don't know. I'm not privy to that information, obviously. If I were part of the WHO committee, I would be looking at all the employees of the Wuhan Institute of Virology. I would have collected blood, and to see if—and they must have stored blood to see if any of them had been exposed to such viruses. That's doable. I would ask for those type of evidence. Maybe they have it; maybe they don't. I just don't know whether they're hiding something, or they're just refusing to open their book for the world to see.

ZIERLER: From the perspective of public health messaging, there have been so many blunders in the United States also, the NIH initially saying that people should not wear masks, the CDC saying in the middle of last year vaccinated people can take their masks off. What for you have been some of the major lessons learned about effective public health messaging as this virus continues to mutate and continues to upend our lives?

HO: I think the U.S. made many blunders. I mentioned earlier China failed to put out the small fire, when it first emerged, and that led to the inferno. But the U.S. perhaps made an even worse mistake. Your next-door neighbor is burning, and you say, "Ah, that fire is going to be put out. We don't need to worry." That is so wrong, and that's exactly what happened under Donald Trump. Next thing you know, our own house is burning. Even with the initial burning of the one corner of the house, our leader said, "That's going to go away. We're going to put it out." And that has been so wrong. We made blunders with lack of testing, lack of masks. I mentioned those before.

The public messaging has been off as well. You cited a few examples about masks early on. Let's take more recent examples. With the success of the vaccines, we did away with the mask mandate very quickly in May of 2021, as the delta variant was just emerging from India and causing devastation in the U.K. That's when CDC, now under a new administration, with new leadership that is thought to be more enlightened, because they were banking on the success of the vaccines, did away with the mandate, and we had a huge surge of delta, with devastating outcome. Then just last week, I'm sure you've been listening to all this talk about CDC not providing the right messaging with respect to omicron and quarantine requirements. It's clear that the message was really dictated not by science but by the commercial or economic factors that needed to get people back to work without deep regard for what is safe. It's easy to be sitting on the sideline and criticizing. I am sure it has been very, very difficult for the decisionmakers. But I think the CDC should have learned by now that you keep the message well rooted in science and keep it very simple, and you need to err on the conservative side until this thing comes under control.

ZIERLER: To turn from criticism to praise, as you look throughout the world, either national governments, government health agencies, or even individuals, who have been some exemplars along the way for getting this right?

HO: Well, I think early on, when the pandemic was just in its first six months, I think governments like China, Hong Kong, Taiwan, New Zealand, Australia, and to some extent South Korea did a pretty good job of containing the spread, largely by applying very draconian measures, so that their population is not affected so much with such high mortality, the kind of mortality we saw here in the U.S., in particular in New York. They did a great job in that respect. I think we still need to give credit to the scientific and biopharmaceutical communities in coming up with the therapies and the vaccines, that praise. And that was initiated under the Trump administration, so folks in that administration deserve some credit, but then followed up by the new administration.

I think even though countries such as ones I mentioned did a great job initially, they actually face a dilemma right now. How do you get out of this? You cannot sustain a zero-COVID policy, unless you say, "I'm going to lock down forever." That's not viable in the long run. Sooner or later, you have to come out of it, and if your population is not well vaccinated, you're going to see what others have seen. This is the dilemma that New Zealand and China and Hong Kong, Taiwan, they all face that, and I don't think they have a solution, because they all have been largely using vaccines that are less than ideal. The only way out, as I see it, is to vaccinate with the better mRNA vaccines, much of the population, very quickly. Because if indeed the rest of the world experienced this omicron wave and becomes largely immune, the world will open up, and those countries which held to a zero-COVID policy will be locked down until they are well vaccinated with a good vaccine.

ZIERLER: I'm curious if you follow in particular what has been happening in Israel. Of course Israeli scientists and doctors really seem to be ahead of the curve in terms of thinking about, for example, right now, a fourth booster. What have been some of the lessons out of Israel, and how might we extrapolate those experiences to the rest of the world?

HO: I think Israel in some ways was wise, or prescient, in that they were willing to pay good dollars for lots of vaccine, so they got in the front of the queue, and therefore in terms of massive vaccination, they were the first, leading the way. They didn't do a lot of basic research, but they did a lot of clinical experiments with vaccinating a large segment of their population, and from practical experience learned that the efficacy of the double vaccination, and then the waning of that protection with time, resulting in information that informed the booster shot from a clinical side. From a laboratory side, I think we knew that, lots of scientists knew that, but they had the clinical confirmation. Now, they're learning, with omicron, because of the antibody evasion properties of omicron, that protection is dropped, unless you're boosted. Then it's restored somewhat. And now, because the boosting has occurred some time ago for them, they see the waning of the protection following the time after boost. Even though they don't have the actual data to say the fourth shot is necessary, they know that the protection is waning and conclude therefore that a fourth shot would be better serving the population. They've been at the forefront of the clinical application of vaccines, because they got in so early and launched the countrywide effort so early.

ZIERLER: Now that we're talking about a fourth shot, is there no light at the end of this tunnel, then? Is there going to be a fifth, sixth, seventh? Where does this ultimately go?

HO: I don't know if it's viable to give a shot every four, five, six months, for this. I think with more shots and perhaps even with some infection on top of the shots, breakthrough infections, we're going to see—this is from the science—we're going to see not only boosting of the amount of the antibodies, but we'll see a qualitative improvement of the antibodies. It's something we call affinity maturation. That, we can detect in the laboratory. It's occurring in a number of people who have been boosted. We think with each subsequent boost, the protection will be better because of affinity maturation of the antibodies. I hope we don't get to that. I think after three or four shots, I think the antibody quality will be so much better that people will be protected well enough not to get really sick. Then, we get into a situation where if much of the population has that level of immunity, then we shouldn't be afraid to catch SARS-CoV-2. We'll get a cold, we'll get a flulike illness, but we'll recover, and we can live with that. That's something we've been living with for decades, for all our lives, with the rhinovirus, with influenza virus, and other respiratory viruses. If we could get to that, then SARS-CoV-2 will not be striking fear in all of us.

ZIERLER: To go back to something you said earlier about one of the things that was remarkable about what would become known as HIV was that this was a new virus that was capable of destroying someone's immune system. With SARS-CoV-2, one thing we haven't talked about, of course, is long COVID, the ability of a COVID infection to harm one's kidneys, one's neurological function. Does that make COVID-19 very different from other respiratory viruses, and even other coronaviruses?

HO: I think we knew from other viral infections that there could be long-term sequelae, but COVID-19 makes that so clear, with so many long COVID, and that's because so many people got infected, and COVID-19, at least in its early forms, was so severe, in particular with the delta variant because it is seemingly more virulent, with more clinical consequences. Now, omicron may not have the same properties. I think time will tell. But we kind of knew that there were all sorts of unexplained long-term consequences that occur in some patients. Not all, but in some patients. With COVID, it seems to be a larger proportion, and it's more obvious.

ZIERLER: The elephant, then, in the room, to push back a little on this idea that at some point a COVID-19 infection won't be that scary, what about the prospect that even if so many people get the infection and they recover from that, we might be looking at a slowly unfolding public health disaster even five, ten years down the line, where long COVID and all of its deleterious effects becomes its own major unique problem even after the pandemic has ended?

HO: I think that's a concern, but at the moment, there's very little we can do about that. We don't know how to intervene to avoid such late consequences, and mechanistically we have no idea how the long COVID symptoms come about. As you say, it does affect how we address the pandemic. Right now, we're only largely focused on the acute problems, whether the virus is going to kill you or not or put you in the ICU for a number of weeks. We don't know whether this new variant that's so dominant now is going to cause the long-term sequelae. There's just simply too many unknowns for us to get a good handle on the situation.

ZIERLER: Because this is such an acute situation right now, where do you see your own expertise slotting in on this national and international effort to understand and combat COVID-19? Where are you contributing?

HO: Looking back on our publications on the subject, we contributed the understanding of how antibodies can neutralize SARS-CoV-2 by developing many of these antibodies and characterizing them and understand how they act on the virus. Then as the variants emerged, first with the alpha and beta variants, and then subsequently with iota, with delta, with kappa, and now with omicron, we have learned how the virus evade the antibodies, and how this then impacts on vaccines and vaccine efficacy. Those are the major subject areas where my lab has made contributions and published papers. We continue to focus on how omicron and other variants evade antibodies, and we try to come up with new strategies to attack the virus. That's the major focus of our current work.

ZIERLER: When you say "we" and "our," who are your key collaborators both within the lab, within Columbia, nationally, or even internationally, who are helping you achieve this research?

HO: I would name a few in particular. Of course, there's my group. Everyone has been working so hard for two years, almost nonstop. Throughout much of the pandemic, half of my lab lived in the dormitories for the students, when the students left school, and for a good six to nine months, much of the medical center laboratories were closed, but our lab was the only one open, and we worked overtime. It's a group of very dedicated and talented postdocs, students, and technicians, who work with me directly. They have worked tirelessly now, for two years. I would give the principal credit to those colleagues.

But within Columbia, we have a group of colleagues who do structural biology, and they work very closely with us. They are led by Larry Shapiro, who is a scientist here, to understand how antibodies dock onto the spike protein, and the molecular details of what's happening. Then that allows us to understand how the viral mutations could escape from the antibodies. That has been a principal collaborator. On the clinical side, we need samples from patients. We need samples from vaccinees, so the Division of Infectious Diseases at Columbia has a bunch of physician-scientists who are engaged in research, and they have been very important collaborators. We needed, early on, some animal experiments, in hamsters, in mice, which at the time was not being done at Columbia, and we rely on people at the University of Hong Kong, whom we have known since the days of SARS. They are coronavirologists who have worked with animals for many, many years, and they helped us do a number of crucial experiments.

Then another example is with omicron. When omicron was reported one day before Thanksgiving, the race was on to characterize it. In order to characterize it, you either have the virus, which we didn't have in the U.S., or you make the spike protein and engineer what we call a pseudovirus. The race was on to see who could do it faster and get the results out quickly to the world. We engaged a synthetic biology group here at Columbia under Dr. Harris Wang, and they synthesized the spike gene for us as quickly as possible. That allowed our team to move as quickly as possible, and from the announcement to the submission of the paper was 20 days, and to acceptance of the paper was another five days.

ZIERLER: This is also warp speed.

HO: Yeah, I've never done anything at that speed before. But guess what? We barely beat people by a few days. Another week, there were a dozen groups reporting the same thing. It's not just us; much of the world, leading researchers, were moving at that speed.

ZIERLER: As a medical doctor, has it been important for you to operate also in a clinical capacity to interface with patients directly, or you rely on colleagues for that work?

HO: I do interface with some cases personally, but I'm not on the front line dealing with vaccinations or patients. I have clinical colleagues who do that full time, and then we work together. But because of my clinical background, I could talk their language and understand situations from their perspective much better than the typical bench scientist.

ZIERLER: Just as a matter of muscle memory, could you moonlight and do a shift in the ER? Are you still close enough to that aspect of your career, or that's really not feasible at this point, you haven't done that in so long?

HO: No, I still provide advice on HIV and SARS-CoV-2, but put me in the ER or in the walk-in clinic, I haven't kept up with all the newest medicines you would use for this condition or that condition. I think I wouldn't want to be the patient that's seeing me in the ER nowadays.

ZIERLER: [laughs] Who have been some of the key funding sources for your COVID research, both government and maybe even in the private sector?

HO: Interesting you asked. When we decided to jump into this and put HIV research on back burner, it really was a bunch of concerned citizens that stepped forward first. First in line was Jack Ma from China, who gave us $2.1 million to get started. Then came a number of other private citizens. In a very short course of time, we got about$10 million of private donations, before we got any funding from large foundations or from the NIH. People like Andrew and Peggy Cherng—Peggy is on the Caltech board; they own Panda Express—they stepped forward and gave us millions to do research on this, because they appreciate how enormous the problem is, and how it's impacting the whole world, and they wanted to do something. It's really those private citizens, philanthropists, that made a huge difference at the beginning, so we could proceed to work without having to worry about expenses.

ZIERLER: What about the NIH? I know you've had such a longstanding and successful relationship with the NIH. Have they been valuable for your COVID-19 research?

HO: Yes. We are now funded by the NIH for the COVID research as well as for the HIV research. Over the years, over my career, NIH is no doubt the major funder, the majority funder of our research. But NIH funding, you cannot mobilize so quickly. As you know, it requires months of grant application preparation then submission and review. The turnaround time at the fastest is about nine months. If you want to get going, you need some seed money from somewhere else first.

ZIERLER: You mentioned of course that so much of the research on AIDS was very important for understanding SARS-CoV-2. From both a resources and a fiduciary perspective, have you been able to put the infrastructure and benefits of the Aaron Diamond AIDS Research Center to use in the fight against COVID-19 as well?

HO: Yes, very much so. I think all the know-how came from HIV research. Our understanding of the spike protein versus the HIV glycoprotein. They're analogous. Technology to develop antibodies against HIV were applied to develop antibodies very quickly. We isolated over 250 monoclonal antibodies to SARS-CoV-2 in the course of two months and characterized them. If we weren't already well-primed by the HIV experience, we could never have done that. Also, the structural studies were all byproducts of HIV research. We simply took the know-how and applied it. The same thing could be said of folks at Caltech. In particular, Pamela Bjorkman's lab had been doing that with HIV, and they too made major contributions in the same way to the COVID pandemic. They didn't lose a beat in making that switch, and many other groups. Now, if you look at who are the most active doing COVID research, they're HIV researchers and influenza researchers.

ZIERLER: For the last part of our talk today, we'll end with some questions that are forward-looking. As you've explained all of these connections that we can elucidate between influenza, between coronaviruses, between HIV, is all of this telling us that at some point in the future we'll have some, for lack of a better term, grand unified theory or understanding of viruses that might have a clinical value across the board?

HO: I don't know if we would have a ground unifying theory for viruses, but we would have a great deal of know-how, a great deal of experience in reacting to future pandemics as quickly as possible, and applying the technologies that have come out of the prior research. Unless we forget it all, I think we will deal with future pandemics more seriously, and with better tools, and with better anticipation. My concern is that if there is an end to COVID-19, we would forget and become complacent once again, and then to think that, "Oh, pandemics are no longer in our future." That would be wrong. History has taught us that pandemics are going to come. Especially with a globally changing environment, there's going to be many, many cross-species transmissions. Yes, we could guess flu, we could guess coronaviruses, we could guess Ebola, but there may be other viruses that are not prominent on our radar screen right now.

ZIERLER: By globally changing environment, you mean that everything from climate change to human encroachment on previously wild areas, the number of different kinds of viruses is only going to continue into the future?

HO: Exactly. Climate change is going to affect the ecosystem of many animal species, and they're going to move about in different ways and therefore change the dynamics of their interactions with humans. The human population continues to grow, and as we grow, we're going to move into previously unoccupied spaces, and therefore enhance zoonotic transmissions. I for one expect more such transmissions and more outbreaks, and so we'd better be prepared. This sort of biological threat is as big as other weapons of mass destruction. We spend so much money on national defense, buying weaponry and developing weaponry, but I think we need to devote a lot more to this type of global threat.

ZIERLER: Is one of the solutions that the future of mRNA technology is to make a vaccine that is so-called variant-proof, or that provides protection for all coronaviruses?

HO: I think the mRNA technology obviously has proven itself to work quite well, in fact superior to some other platforms. That's good. It's also very adaptable. You could apply it very quickly. Once a new pathogen has been identified and sequenced, you could apply that information very quickly into your mRNA platform, in a matter of days, and therefore start testing only a week later. It's great in that respect. Then the FDA has said that they will treat it like flu vaccine; if the fundamental platform is the same, but you need to switch in a new sequence, you don't have to go through a whole array of clinical trials. That will shorten the timeline. That's going to be great for dealing with future outbreaks. Whether it will be the ultimate solution to deal with variants, that depends on the fundamental properties of the virus.

ZIERLER: As a beneficiary of these different resources yourself, what do you see as some future lessons we can take where we look at the partnership of research coming both from private benefactors and public research organizations?

HO: I think it's going to be a continued collaboration, cooperation among all these sectors. The academic labs will drive a very crucial component, particularly in the early phase, identifying pathogens, sequencing them, getting the information out, characterizing some immune responses and all that. That's largely in the realm of the academic labs. But once information is clear enough, I think there's no doubt we need to continue to rely on the private sector, particularly in biotech and pharmaceutical companies, to take it further. The academic labs, there are some that try to do that, but generally don't do it as well as what industry can do. But the industry—COVID-19 is a clear example—they face enormous risk. They could spend billions and get nothing. In order for them to commit fully, the government has to step in. In this case, the government stepped in for some of the vaccines, some of the antibodies, and mitigated the risk for some of the companies, not all, and that was really helpful. For the academic labs, the private sector was really crucial, in the citizenry, the private philanthropists. They really got us going fast, and I know labs at Harvard and other places got going because of individual donors. I think we are going to need all that to confront future outbreaks.

ZIERLER: As you mentioned earlier, the public health risks that we face really can be likened to weapons of mass destruction. Of course, one of the major questions in the 21st century, if it's going to be a century of peace and safety or not, is how the future of the United States-Chinese relationship will go. From a public health perspective, where are you optimistic about partnership between the two superpowers, and where do you see cause for concern?

HO: There's just too much tension right now between the two governments, so I don't see a lot of cooperation. That's a problem. If you cannot cooperate on public health, what else could you cooperate on? That's the most logical space—for human health, for the benefit of humanity. This is the perfect realm to work together, and yet it's pretty clear we're not doing a lot of that. The scientists are collaborating among themselves on both sides of the Pacific, but there's hardly any government-to-government collaboration. That's a shame. This is not one side of the aisle versus another side. I think both sides, Democratic and Republican governments or officials, are largely anti-China. Some of that is for good reasons, whether it's human rights or their autocracy, but I think there is also, I must say, a lot of misunderstanding of China, and vice versa—misunderstanding of U.S. on the Chinese part. I see a real problem of growing nationalism on both sides, and that's just going to make things even worse.

Also, there's this initiative that's launched under Jeff Sessions called the China Initiative, that targets Chinese or Chinese-American scientists, and view them as spies, here to do espionage on behalf of China. That's a total disregard for reality, when many are major contributors of American science. That's really enhancing the tension that exists between the two countries. So a lot of the ills of America, I think the politicians would like to blame it on China, some of it justified, a lot of it not justified. If the Chinese are willing to do some of the manufacturing that we don't want to do, and then we have to import it and pay the price, that's part of our own doing. Now, at places like Caltech, a lot of the scientific contributions come from foreign scientists, and the Chinese contingent is a dominant part of that. To drive them away is to decrease American competitiveness. This China Initiative is doing exactly that. That's not going to help.

ZIERLER: Finally, for you, last question for today, for however long you define or extrapolate your research agenda—one year, three years, five years—when do you think you'll be done being so consumed with COVID-19 research and perhaps are you looking forward to getting back to AIDS research at that point?

HO: I'm looking forward to doing HIV work again. We've been planning to do that—December of 2020, I had a lab meeting to focus on how we would get back and outline the projects that we would kickstart once again. Then the alpha and beta variants came, and we got immersed in COVID again. I would say this October or November, we were thinking of doing exactly the same again, to say, "Okay, let's take the old list out and figure out what we're going to do in 2022." Then omicron came, and now we're neck-deep again. It's an aspirational goal right now to get back, but the reality is we have so much ongoing with COVID-19 that I don't see giving that up for the next year or two. Hopefully in 2022, we will really start some of the HIV research, try to strike a proper balance between the two subjects.

ZIERLER: For everyone's sake, I hope you can get back to it as soon as possible. David, this has been a phenomenal conversation. For our next discussion, we'll go all the way back to the beginning, trace your family origins and childhood. Thank you so much.

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Tuesday, January 18th, 2022. I am delighted to be back once again with Dr. David Ho. David, it's great to see you. Thank you for joining me again.

HO: My pleasure.

ZIERLER: In our last conversation, we did a wonderful tour of your approach to the science and the research. Today, I'd like to go all the way back to the beginning and trace your family background. Let's start first with your parents. Tell me a little bit about them and where they were from.

HO: Let's start with my father. My father was born in 1919, in the midst of another pandemic, [laughs] in a province called Jiangxi in southeastern China. He was born to landowners in a rather rural area of that province, but he managed to go to school, in fact went to the provincial capital for his middle and high school experience, which was rather rare. Then he went on to college at Saint John University, which is actually a very distinguished university in China, but his university experience was interrupted by World War II, when Japan invaded much of mainland China. His university kind of moved from the city of Hangzhou to various places and ending up in Western China. In fact, he studied many different things—math, engineering, and English, and helped to serve as a translator for American soldiers. It took him actually longer than the usual to finish his college because of the War, but he did finish up in 1947, and graduated. Then on a whim, he and a classmate thought they would go to Taiwan for a holiday after their graduation, and so they took a ship and went to Taiwan. This is right after the War, and Taiwan was transitioning back to China from Japanese occupation since 1895. The locals spoke the Taiwan dialect plus Japanese, and they were in need of people who could teach Mandarin, so my father was actually asked to stay and teach Mandarin, and teach English. He stayed, initially in the northern part of Taiwan, and later was called to teach in similar capacity in the middle of Taiwan. That's how he met my mother.

My mother, on the other hand, was born in Taiwan, in 1931, so about 12 years younger than my dad. Her family had for many generations been living in Taiwan, so she was brought up under the Japanese educational system until 1945 and spoke Japanese and Taiwan dialect fluently. She was finishing high school when my dad happened to be teaching in that high school. They met because of that, but my dad did not approach my mom until after she graduated. [laughs] To make a long story short, they were married a year or two later, and I was born a year or two later.

ZIERLER: In the late 1940s, with all of the political upheaval in Taiwan and on mainland China, what were your parents' politics, or what were their political affiliations?

HO: My father obviously, translating for American soldiers, had to work with the nationalist government, the so-called Kuomintang or KMT. But ideologically—well, not necessarily ideologically—he was aware of the corruption of the KMT government. He was not really pleased with it, nor was he all that pleased with the communist side. I will just tell you that for a mainlander to go to Taiwan and marry a local, that was a mixed marriage back then. Even though they were all Chinese in heritage, that was considered a mixed marriage and it was really frowned upon by the local Taiwanese in particular. The Taiwanese were fairly sophisticated, because of the Japanese experience. They were more developed than the mainland. The first wave of mainlanders were primarily soldiers, in fact peasant soldiers, by and large, and not very well-educated. There was sort of a class difference, so my parents were among the very early mixed marriages.

To make a long story short, they got married, they had me, and then two years later my younger brother. I was born in 1952. By 1957, my father had already decided that he was going to seek advanced education in the U.S. He applied and got in and ultimately left us behind to come to the U.S. on his own. It took him about a month on a boat to get to the U.S. and he went through various places in Washington state, in Colorado, in Arizona, before ending up at USC, where he studied engineering and worked part-time. He worked for himself and to send money back. Believe it or not, he sent $50 back each month, and that was sufficient to cover our expenses back in Taiwan. ZIERLER: During this time, did your mother work outside of the house? HO: Yes, for a period she worked for the equivalent of the tax office in the city of Taichung where I grew up, but that did not generate a lot of income [laughs], I must say. The$50 went further than what my mom made.

ZIERLER: Was his intention to bring the family with him to the United States, or to bring the degree back to Taiwan?

HO: I think in the beginning it was uncertain. He certainly wanted that advanced degree and outside education, but once he got his advanced degree in engineering, he had job opportunities in engineering in the L.A. area, and so he stayed. Once he stayed to work, I think his goal was to get a green card for himself, and for us. This will require a little bit of American history, but you may know, in the late 1800s, there was a Chinese Exclusion Act that was passed, actually largely initiated from California, and largely related to Leland Stanford. The Chinese were excluded by that act from becoming immigrants until 1942 or 1943, during the War, when such soldiers were needed. It was partially repealed during World War II, but it was never fully, because what remained was a quota system, and that quota system allowed a few hundred Chinese to become immigrants. But in 1965, it was fully repealed by Lyndon Baines Johnson, with a ceremony, signing that, on Ellis Island, actually. When it was fully repealed, that actually allowed me, my brother, and my mother to come, as immigrants, in March of 1965.

ZIERLER: Given your parents' linguistic abilities, in early childhood, what languages were spoken in your house?

HO: My first language is a Taiwan dialect, and my mother and her mother spoke Japanese, so I picked up some Japanese, but I'm not fluent in Japanese. Then once I got to school, I learned Mandarin. My education went from kindergarten to sixth grade, so basically went from the period when my father left until the period when we rejoined my father in 1965. For an eight-year period, we were without my father, and we did not see him a single time. He never returned until we reunited in Los Angeles, actually.

ZIERLER: Did you speak to him on the phone? Obviously this is before Zoom and email.

HO: No.

ZIERLER: You really had no relationship with him?

HO: We didn't have phones at home, and very few people had phones in Taiwan at that point in time. The communication was a weekly letter that he wrote to us, and we wrote to him. Some of the letters each month would have a $50 bill in it. That's how we communicated. Of course occasionally, there would be pictures sent along. ZIERLER: What was the setting like in your childhood? Was it urban? Was it rural? Did you live in an apartment, a house? HO: We lived in a tiny house at the edge of the city. The city, Taichung, today, is a pretty big significant city, over a million-and-some people. But back then, it was a small town, you would say. We had a train station, movie theatre, and so on. I didn't speak a word of English. English was not taught in school. I didn't even know my ABCs until I got to Los Angeles. It was a different world back then. [laughs] ZIERLER: What was your school like? Was it a small school? HO: No, the schools were large. I would say in my class, we probably would have certainly more than 50 students and maybe closer to 70 students per class, and there were multiple classes per grade. It was a huge school. It went from first grade through sixth grade. I think in first, second grade, I was not such a great student, but by the later years, I was a pretty good student. ZIERLER: Were you particularly interested in science even as a young boy? HO: I was curious. Somehow, I was good in math. Science was never taught as a formal subject in elementary school. But my father was an engineer. I had an uncle who was a chemical engineer, who also went to Caltech, by the way. He went there for his chemical engineering degree. He was abroad as well. He didn't go as early as my father, but he went while I was still in elementary school. That's an uncle on my mother's side. That had some influence on me. I must say in the 1950s, there were two Chinese physicists, C.N. Yang and T.D. Lee, who won the Nobel Prize in theoretical physics. Of course that was made a big deal in Taiwan, for the students, and they were lauded and praised, and worshipped, in fact. I think that had an impact on me because from that point on, it was ingrained in me that there were scientific heroes of great distinction, not just locally, but internationally. I suspect that had some impact on me as well. ZIERLER: When you got the news that you would be reunited with your father in California, did you understand at the time that that meant a permanent move to the United States? HO: It certainly felt permanent to us, in the sense that we sold the house. All our belongings were largely gone except for three suitcases, maybe. That felt very permanent. Up to that point, we had never traveled anywhere more than an hour or two away from our home. Here, we're taking a trip that would take us to Japan, Hawaii, then Los Angeles. I had never been on an airplane until then. I never had really seen a television until I got to a hotel room in Tokyo, where we spent one night. The world dramatically changed for us. ZIERLER: What were your feelings? Were you excited? Were you nervous? What did it feel like to embark on this adventure? HO: Actually, probably both, I would say. There was a lot of anxiety about what lies ahead, but America was put on a pedestal by those in Taiwan in terms of its development and advances in all sorts of things—technology, science, medicine, what have you. It was so ingrained in us that it was largely viewed as a great opportunity, and people would have died for such an opportunity, so naturally as kids, we interpreted it that way, largely. But we knew that we had to learn a new language. We had to adjust to a new environment. Even as a child, you would have a lot of trepidation about that. In fact, we did, and the early months of that experience certainly were not easy. ZIERLER: Was your father finished with his education by the time you reunited? HO: Yeah, my father is so conservative about things, he got a job already, was in the process of buying a home. He wanted to give us that stability. Believe it or not, the home was not ours to have until—there's a long process—when we first arrived in March. He had lived in somebody's attic, almost, next to USC, and that's the Watts area. When my brother and I first came and entered the school system, at sixth and fifth grade respectively, we were in school with all Black kids. Of course, we didn't understand what they were saying, and they had no way of communicating with us. From there until the end of that school semester, we were in the Watts area going to an American school with African American kids. Later that summer, we moved to our home, which was in the Silver Lake area, a tiny home, a two-bedroom home, one bedroom for my parents and one for my brother and me. Then we started school in a more diverse environment with perhaps about half the kids being white and then others being African American, Hispanics, and Asian. It was a good mix and it was a good experience. ZIERLER: Do you have a clear memory of seeing your father for the first time in America? HO: Oh, absolutely. We arrived via Hawaii on March 2nd, 1965. It was in fact that same terminal that is part of the American Airline terminal today at LAX, and it has that long, long corridor—you exit into the luggage area—and it still has some of the tiles from that period. As I've traveled through LAX many times, that corridor is still there. I still remember it vividly. My father was walking up that corridor, and we were walking in the opposite direction and met. Of course it was very emotional after eight years. ZIERLER: Did you feel like you were meeting a new person, or did you remember him from earlier in your childhood? HO: I remembered him primarily from pictures, because when he left, I was five. Yes, there's some vague memories, but they're not all that clear. I remember him from more the pictures that he would send occasionally. He probably of course only recognized us from pictures because I had grown from a 5-year-old to a 12-year-old. It was a very emotional reunion at that long corridor at LAX. ZIERLER: How did your mom do with the relocation and the readjustment? HO: My mom is a tough lady. I think she did well. Of course, she had to learn English as well. She didn't know much English, although she did study the ABCs when she was in school, in high school and so on. She had to learn a new language, a new way of living. The supermarket is totally different from the markets that we shopped at. We rode a bicycle everywhere, and now my father had a car, but she didn't know how to drive. In L.A. in particular, you needed a car to get anywhere. Our world was—I wouldn't say turned upside down, but it was totally different and required lots of adjusting. ZIERLER: What was your father's work after he finished his degree? HO: He worked for various companies—Bell & Howell, and Xerox, and various engineering type of jobs, and he continued to do that. Later, after he retired, he actually devoted his entire effort to using an American computer, with a keyboard, to type Chinese. He actually was one of the earliest to devise a way of typing Chinese using a standard computer keyboard. That is his major contribution, I think. A lot of what he did earlier was built on by others to come up ultimately with the current system of using a regular computer to type Chinese. ZIERLER: How quickly did you find yourself becoming Americanized? Being fresh as an immigrant as a 12-year-old, what was that process like for you? HO: It was tough at the beginning, of course, not being able to communicate, and being a rather good student to the dumbest guy in the class, initially probably a pretty bubbly, outward-facing child, to an introvert, because of the inability to communicate. That was a tough adjustment. But I would say a few months later, certainly by six months, I could understand just about everything that's being said by kids and by the teacher, at least largely. If I didn't understand anything, I'd follow enough of it to know what to do. I think in terms of feeling like other kids, probably after a year. By then, I could catch up with whatever needed to be done in even—forget the math class. The math class was extremely easy compared to what we had to go through in Taiwan. I think by sixth grade, we had learned everything that the middle school in America was teaching, so the math was a piece of cake. But history and English, and back then we had shop, all those things were rather new. But by a year later, I think I was managing. ZIERLER: Were television and movies useful for learning English? HO: Oh, absolutely. In fact, it was by watching television that I realized that I had followed for the first time several sentences with complete comprehension. Of course we tried to watch the news. My father watched the news religiously, and that's helpful. In the beginning, it was just going over my head, but gradually, I realized I was absorbing more and more. My brother and I watched sports, and that was helpful, and we'd watch a lot of cartoons, and that was helpful. And this sounds silly—even watching Three Stooges was helpful to our English. Aside from all the noises they made, we comprehended—their level of English was at just the right level. [laughs] ZIERLER: [laughs] You mentioned of course in Taiwan, science was not taught formally as its own course. By the time you got to middle school and were taking biology and chemistry, did that put you on a track in science, even at that age? HO: No. Back then, the middle school was not teaching biology or chemistry. It was teaching what they call science, so it was a potpourri of different scientific subjects, at pretty rudimentary level. So at least back then we didn't have the formal biology, chemistry, physics, or algebra, trig, and calculus, until high school. But I remember I was already inclined to learn more about math. The math in middle school in L.A. was too simple, and so I remember every weekend taking a bus from our home to the downtown main library to borrow books on math and on some science. I must admit that a lot of the books I borrowed I couldn't comprehend it, but I had a special interest in learning more than what the school was teaching. ZIERLER: Tell me about your high school. What high school did you go to? HO: I went to John Marshall High School, which is in the Griffith Park area, just in the foothills of the Observatory there. It was a very diverse school. We probably had 400 kids in our class, or thereabouts, and yet it was academically quite strong. In fact, for many years thereafter, John Marshall High School was one of the top-performing academic public schools. As I mentioned earlier, same as the middle school, it's quite diverse. Certainly a majority white, but a large segment of Hispanics, African Americans, and Asians. I think Asians would have been maybe 10%, 15% of the student population. It was a good environment, and I had good teachers, particularly in sciences and math. I think that helped me a lot. By high school, I was pretty much adjusted and was able to elevate myself to higher-performing students. ZIERLER: As your father's career progressed, was your family moving up socioeconomically? HO: Yes, I would think so, and my mother, she then initially worked in a jewelry factory downtown, and took a bus every day there, and worked eight hours. She's a pretty tough and capable lady, and so very quickly she rose to be a manager, taking care of maybe managing 100 different workers for a jewelry company. This is commercial jewelry that's sold on a large scale. She managed a lot of people very quickly. She helped to generate income for the family, and also two years after we arrived in the U.S., another sibling came, and he's a brother who's 15 years younger than I am. ZIERLER: In the late 1960s, with all of the unrest in the country, the political, the racial unrest, the Vietnam War, as an immigrant, was it hard understanding these things, or by that point, were you fully assimilated and you felt like you were a part of these issues? HO: Yeah, maybe in the first couple of years, I was not as tuned in, particularly because I was still younger, but certainly by the time I reached high school, my English comprehension was pretty much the same as the other kids by then, and the issue of the Vietnam War was certainly prominent to all of us. The campus unrest at Berkeley and other places was always on display every night on television. The 1968 Democratic Convention, I sat there and watched almost all of it every night, feeling rather indignant about what transpired. I certainly was influenced to think that that war was pretty unjust. I never became one of the major protesters on campus, but I certainly had that sentiment. ZIERLER: Did the racial unrest in Los Angeles reverberate either in your high school or your neighborhood? HO: Yeah. We had just moved out of Watts when the Watts Riot occurred. We obviously watched that on television for a number of nights. That became a very prominent issue. Of course, some time later, we had the further unrest related to the assassination of not only MLK, and we just celebrated his birthday yesterday, and we also had the assassination of Robert F. Kennedy. I was a high school student during that period. ZIERLER: When it was time to start thinking about colleges, was Caltech the be-all and end-all, or did you apply more widely? HO: I applied widely, but in those days, widely means four schools, [laughs] unlike today, where kids could apply to 30 or 40 schools. Yes, Caltech was certainly prominent. I was interested in math and science, so Caltech and MIT were the most prominent schools on my list. Being in California, Stanford was on my list, but Stanford back then was not as highly regarded or as highly competitive as it has been more recently. My backup school was UCLA. Those were the schools I applied to. I think Caltech had an impact on me because it was close, I had been on the campus, and it had these figures that I had looked up to, like Richard Feynman and Murray Gell-Mann, and such prominent figures. Back then, I was more interested in physical sciences, so those names jumped out. It's hard to believe UCLA is so difficult to get into nowadays. Back then, it was a backup school for many of the better students. ZIERLER: What were your impressions when you first arrived on campus in Pasadena? HO: I always knew it was a small school by comparison, without the excitement of football, basketball games that would attract large audiences. I pretty much knew what I wanted to do, not in any specific area, but pursue something quantitative in the sciences. Caltech was more or less what I expected—that it would be very intense, very focused, and one had to match that intensity, in particular the focus on excellence. ZIERLER: You mentioned in your high school, Asian students or students of Asian American heritage comprised 10% or 15% of the student population. Was that roughly a similar ratio at Caltech at that point? HO: No, I think it was lower at Caltech. First of all, my class was the first one to allow women, or girls. There were very few females in the class. I could think back and probably recall most of the Asians, so it probably was no more than a dozen out of a class of 180 or so. It would be less than 10%, I would say. ZIERLER: Did you live on campus or did you commute from home? HO: I commuted from home, although I was assigned to Ruddock. Although that name, I know, is changing. ZIERLER: Yeah. What was the game plan for you from the beginning? What kind of science did you want to pursue as an undergraduate? HO: I think I was influenced by the fact that as you move from biology to chemistry to physics, physics was more pure, and more challenging, maybe biased by the fact that many of the students in high school kind of drop out by the time you get to physics, suggesting that it is the toughest challenge. I went to Caltech with that in mind, but I quickly realized that there's very interesting science in many different disciplines. I still love to read about physics and astrophysics and theoretical physics, but from the sideline, basically. When I got to Caltech, after a year or two, I also realized that biology was rapidly evolving. That's the advent of molecular biology. One could readily see the impact on biology on life science and on medicine. Every time I talked to people about my interest in physics, it seemed so abstract. While everybody recognized that that's really pursuing very challenging pure science, they always had trouble understanding why one would pursue that. Gradually, that changed me to think about pursuing science, but also pursuing something that's more tangible to the layperson, and to myself. That, certainly by third and fourth year, changed me to think about doing research, not in physics, but in life sciences, with an application. That ultimately led me to apply to medical schools. ZIERLER: These revolutions that were happening in molecular biology, were there any professors at Caltech who were particularly influential, or who you felt were operating at the vanguard of these advances? HO: One that comes readily to mind is Max Delbrück, who was a physicist turned biologist and became a Nobel Laureate in biology. I think he applied his physics and quantitative background to biology in a unique way, and thereby making a major contribution. He was a senior figure and very inspirational figure. My first course in biology at Caltech was taught by Lee Hood, who at the time was a younger professor. He taught molecular biology and biochemistry in a way that was drastically different from the biology that I knew from high school. Biology from high school was mostly botany, zoology, remember the names, and you categorize them into different species and families, and so on. I thought that was the least interesting class when I went to high school. ZIERLER: It was like stamp collecting. HO: Right. History was more interesting than that. But when Lee Hood and other faculty members jointly taught biochemistry, it was fantastic, because they were teaching us new ways of thinking about biology. The DNA structure had been solved, how DNA is transcribed into RNA, which in turn are translated into proteins, and how proteins can function, the genetic code. All those things were fascinating. They taught the class in a way that didn't just tell you, "This is how things are." They taught in a way of, "This is how things were discovered." Then in our take-home assignments, we were asked to solve the same problems that the prior scientists were solving. It was a real-world experience, and to me, it was just as fascinating as how mysteries in physics were solved. Here, you are working on something that impacts not only on your own body but those around you. The translation to medicine was immediately apparent. ZIERLER: Obviously Lee Hood was operating in a very multidisciplinary way. Was anybody at Caltech thinking about biophysics at that point? HO: I would say yes, the term came up, but it was mostly in the context of structural biology. At that point, only x-ray crystallography approaches were available. Of course Watson and Crick and x-ray crystallography helped solve the DNA structure, but that was also being applied to proteins. But it was biophysics in a different way. Lee Hood, at that time, was not so involved with the technology that he was later famous for, for developing the DNA sequencer. That came long after I had graduated. ZIERLER: What about virology? Was anybody working on viruses while you were an undergraduate? HO: Yes, there were biologists who worked on viruses, but it was not as prominent a subject back then. A lot of the virologists typically worked at institutions that had medical centers linked to them. Caltech certainly did not fit that bill. Virology was there mostly as an instrument for studying basic science, basic molecular biology, not so much focused on diseases. ZIERLER: In the early 1960s, of course, Matthew Meselson was conducting groundbreaking research on mRNAs at Caltech. Did you sense that that legacy was there, when you were an undergraduate? Did Caltech feel like a center of mRNA research? HO: I probably wasn't so focused on mRNA, per se, but it was a center for lots of new biology or molecular biology and cell biology research, certainly, and genetics. That's how I viewed Caltech life science. ZIERLER: Tell me about more broadly the social scene at Caltech. Obviously it's not a place like Columbia or Berkeley in the late 1960s and early 1970s. Was there any political activity going on, any anti-war sentiment? HO: Oh, there definitely was, among faculty and students. But there was not the disruption to classes that went on in places like Berkeley and many other institutions. But I think the dominant sentiment was in support of the student protests, and that's not limited to just other Caltech students but quite extensively among the faculty as well. That's what I recall. ZIERLER: Tell me about some of the lab work that, looking back, was really formative in your interest in taking a clinical approach to biology? HO: I would say the lab work I focused mostly on was doing electron microscopy in the basement of the old building. I worked specifically for Jean-Paul Revel, who was on the faculty for a long time. Of course, he's long gone. He just let me do what I wanted to do, looking at the structure of how cells attach to a substrate, and how cells come in contact with one another, and how they may communicate. My senior thesis was focused on work done in his lab on cell-cell contact and communication. I spent many, many hours in the dark, in the microscopy room, studying pictures, and he guided me throughout that process. We published one paper, as an undergraduate. That was my first publication, so it left a deep impression, and began to form my interest in wanting to do biological research at the bench. ZIERLER: Of all the things that you could have worked on in the laboratory, why this topic? Why did it speak to you? HO: It also had to do with which faculty members had room to take in students. Jean-Paul Revel had just, not long before that, come from Harvard Medical School, and he taught anatomy and other things, so he had more of a clinical side to him, and he was willing to take me in. It's a combination of different factors that I ended up in his group. ZIERLER: What was Revel working on himself at that point? HO: Still cell structure, cell cytoskeletons, cell communication. What I did was more or less consistent with his lab interests. ZIERLER: What were the big questions at this point? What was the frontier of knowledge? HO: I would say it was mostly extending the knowledge from the DNA structure, the genetic code, and how this whole machinery worked, then thinking about how to get deeper into the science, and then, very quickly after that—by the early 1970s, the idea of taking it further, to see if we could then manipulate genes. It's the beginning of the idea of genetic engineering. ZIERLER: Even at this very young age, I wonder if you were thinking at all about biotechnology, for example? Or was Caltech and the environment that you were operating in what Lee Hood called "small science," for the most part? HO: I think we only knew small science back then. [laughs] The big science didn't come until some time later. I wasn't thinking about biotech or pharmaceutical. I was just thinking about life science, and how life science may be useful when applied to medicine. I was already focused on going to medical school, learning what a doctor needs to learn, but I went to medical school not with the intention of becoming a practicing physician, but a research scientist. I wanted to do academic medicine, to do research and then to apply that knowledge to medical care. ZIERLER: During the summers, did you work in labs, as an undergraduate? HO: Yes, I just worked in John-Paul Revel's lab. ZIERLER: Now the decision to go to medical school, to what extent did you come up with that on your own, and to what extent were there mentors, people like Lee Hood for example, who did that very same thing, went on to medical school with the intention of pursuing research? HO: I think it certainly was not inspired by Lee Hood's example, because Lee Hood is not your typical physician. [laughs] He's more of a scientist. But I think I just liked the idea of doing cutting-edge research that could advance medical care. I had no idea which precise area I would work in, so it was mostly coming, I think, from myself. If there were external influences, I don't recall them now. ZIERLER: Did you have any interface in a clinical environment as an undergraduate? HO: Not really. At that time, Caltech did not have all the affiliations that it has currently. ZIERLER: For the last part of our talk today, just retrospectively, in light of your love of Caltech and your devotion and support of Caltech, what is it about it that made your undergraduate experience so special and has inspired you subsequently to remain so connected to Caltech? HO: It gave me a great education, and it's a model that's different from all the other schools that I have attended, including Harvard Medical School. We seldom had in-class tests. We had take-home tests. We were asked to utilize textbooks, whatever is at our disposal, to solve a math problem or a science problem. Or in the humanities, we were just asked to do a project, to research an area and write it up. That is more like the real world. By memorizing a whole bunch of things, yes, it's important that you know some of the basic knowledge and have them filed away, but a lot of the real-world problems, you can open any book you want, and use any information you can obtain, and apply it to solve a problem. That's what Caltech education was to me. We did that on a regular basis for nearly all the classes. You become adept at thinking through a problem and how to tackle it. It's the problem-solving process that I learned the most, and that's what I use in my scientific career more than any education that I attained at Harvard Medical School. Because medical school, at least in the first couple of years, it's memorization of a lot of things, which you learn, and you learn to take tests, but the bulk of it, you forget. You know where to look it up, and so you can recall that information fairly easily. But in today's world, with this, you can get everything. The problem-solving skills and the logic, the logical thinking, the reasoning, are what you need, certainly in science, but also in many other disciplines. ZIERLER: For all the work that you've done subsequently, the way that Caltech taught you to problem-solve and to think, really, has stayed with you? HO: Yes, it's what I use every day, in pursuing our science. I must say that Caltech also gave me a great quantitative background. We were required to take so much math, and because of my initial focus on physics, I took more math than most biologists. In our research in the course of HIV and now in the course of COVID, I have a more quantitative perspective than most of my colleagues, and our most seminal work in HIV, to come up with an understanding of the dynamics of the virus replication, was strictly simple calculus, done in a way that nowadays a high school student could do. But most biologists were not doing that, and it is again that Caltech education that led me to understand the quantitative aspect of HIV replication. Having that info and applying it to the treatment arena—that led to the major advances in treating HIV. ZIERLER: Last question for today—what medical schools did you apply to, and why ultimately did you choose Harvard? HO: Let me think now. I also applied to very few medical schools, unlike today's students. I recall applying to UCLA, UCSF, Stanford, and Harvard. I don't think I applied to any others. I got into all of them, and I chose Harvard because of its strong science as well as strong clinical medicine. ZIERLER: We'll pick up next time when you arrive in Cambridge. [End of Recording] ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Tuesday, February 1st, 2022. I'm delighted to be back with Dr. David Ho. David, as always, it's great to see you. HO: Good to see you. ZIERLER: We're going to pick up on when you get to Harvard for medical school. But first, a very timely question. As you know, of course, Moderna just announced that they are launching clinical trials for the HIV vaccine. I'm curious if you're involved in this research at all, if there are any breakthroughs that have allowed for these clinical trials, and if there is any hype associated with the press release given how difficult creating a vaccine has been for HIV. HO: I think Moderna has their new platform technology, so why not apply it to many things, and HIV is one of those intractable problems, for vaccine development, so it makes sense to try. Do I think it will overcome the challenges that we have faced for several decades? No. You're showing the immune system the same molecule just using a different delivery strategy, but the fundamental problem is with the structure of the HIV envelope protein. So it's something that must be tried, to see if you get an unexpected result, but the expectation would be that they will face the same structural problems that the field has been facing all this time. ZIERLER: Now when you say a new platform that Moderna has, what does that mean? HO: The way we showed the spike of COVID-19 virus to the immune system is now largely using viral vectors or mRNA. Those are just the delivery platforms. Or, you could give the protein itself; that's another way. But if you give the RNA, the RNA will make the protein, and the protein will be presented to the immune system. If you use a so-called viral vector, like the Johnson & Johnson vaccine, that delivers the gene to the muscle, and the muscle will make the protein and show it to the immune system. But the fundamental problem is that molecule that is then presented to the immune system, is covered with sugar, covered with variable sequences, so that the type of immune response you elicit will be very, very narrow. And HIV is—all the viruses out there are rather diverse. You could protect against the version that you show to the immune system, but you won't be able to protect very well against other versions. That's a problem. I don't think that's a platform problem, but they're using the platform to see if that will help. It's the logical thing to do, but it alone will not overcome the problem. ZIERLER: It's a moonshot in the sense where it's very much worth at least trying, is what you're saying. HO: Yeah, it has to be tried. ZIERLER: Let's say there's a miracle, and it works. What would that look like? How would it work? What would be different now than all of the work that has been done trying to achieve a vaccine so far? HO: That would be close to a miracle, if it worked. Then we'd really have a solution to the pandemic. You would try to scale that up and administer it initially to all the high-risk people. You have to do the trial to show that it indeed protects. That's going to take many years, by the way, because this is not COVID, with cases accumulating so rapidly so you can have the end result read out very quickly. This will be years in development and years of trial. So even if the strategy works, I think the vaccine is five-plus years or more away. ZIERLER: Let's go now back to Harvard. The first question there is, were you open to the idea of pursuing a medical degree to becoming a medical doctor, or did you know even from the beginning that this was the step that you wanted to take on your way to a career in fundamental research? HO: I think there are times where you vacillate, but largely, I was leaning toward a research career in an academic center, and probably one focused on important medical diseases. Over the years, my interest within that area had varied from something as diverse as cardiology versus infectious diseases. ZIERLER: Coming to Los Angeles, being at Caltech, how widely traveled were you in the United States? When you got to Cambridge, had you seen other parts of the country before? HO: I had seen parts of California [laughs], driving around. Have I gone—? No, I've not gone to any other place outside of California. We talked about this. I had never traveled outside of Taiwan, and then coming to the U.S., going through Japan and Hawaii, that was the first flight I ever took. The next flight was some years later, to Cambridge. ZIERLER: What were your impressions of Boston when you first arrived? What did you think? HO: It's very different from L.A. It's much smaller. I had a bike and I could get around Boston and Cambridge on the bike. It was very efficient. People drove like crazy, people in Boston. L.A. I think by comparison was very law-abiding when it comes to driving. Boston, there are lots of crazy drivers. Boston is dramatically different, because it's such a college town, with so many schools. The whole population seemed young. Then the reality of a winter in Boston hit sometime later. [laughs] ZIERLER: [laughs] Did you have any opportunity for lab work in those first few years, given how important the research was to you, or was it all classes? HO: No, there was no lab work for the first two years or so. They were all classes. Any serious research work only occurred in the fourth year of medical school. The schedule is so tight. There's hardly time for anything. Then when I got to the fourth year and tried to do a thesis, it's only a course of a few months, so you can't get anything serious done in the laboratory. It turned into a review of a field, summarize the current status, and that sort of thing. Nowadays, it sounds rather superficial. ZIERLER: I'm curious if in graduate school all of the revolutions that were happening in biology—reverse transcriptase, recombinant DNA—if these things were registering with you, in medical school, as opposed to being in a PhD program for biology. HO: Yeah, they were registering. I was at Harvard, where research is emphasized, and I was in a program called Health Science Technology that's joint Harvard Medical School and MIT. We had our courses being more quantitative, more research-oriented, and more cutting edge topics coming up, so I got a lot of exposure. When you do the biochemistry in medical school, that had a lot of modern molecular biology in there. ZIERLER: What were some of the big questions that you wanted to pursue? Besides just doing well in the classes, what were you hoping to get out of medical school in gaining this education? HO: It was not so much focused on a particular discipline, but when you go through the medical textbooks, you realize that we knew a lot about anatomy, physiology, but then when you go into diseases, many of the diseases remain totally unexplained. Yes, some of the infectious diseases are obvious; we know what the cause is, and fortunately, for many of the bacterial and fungal infections, we already had treatment. But for viruses, there was hardly any treatment then. For many, say, neurologic or rheumatologic diseases, we sort of understand what mechanism may be at play, but the fundamental cause was unknown, and for many of them, still unknown today. Yes, we know Alzheimer's is associated with these plaques, but what triggered them? And various other neurodegenerative diseases, they're still mysterious. Something as common as multiple sclerosis, we still don't know what the cause is. Yes, it may be triggered by infection, followed by some autoimmunity. We have some vague notions as to what might be going on. Same thing with lupus or arthritis. Rheumatoid arthritis, the body is attacking the cells, but what triggered it? We still don't know. What intrigued me as a medical student was, well, what about these remaining medical mysteries? How do we understand them? And finding a cause. Because the ultimate solution is understanding what the fundamental cause is, so that's what I was interested in. For a moment, I was interested in multiple sclerosis. The next moment, I was interested in something else, depending on the course I was taking at the time. ZIERLER: What were some of your more enjoyable courses and formative influences from the faculty, the professors at Harvard Medical School? HO: I enjoyed courses that were more quantitative, and that's because of coming from Caltech, that's more familiar to me. For some of the cardiovascular courses or pulmonary, it's very mechanical. There's either fluid dynamics or air dynamics, and the track I was on at Harvard Medical School was very quantitative, so it brought a lot of those type of applied physics and also mathematics to those disciplines. In the end, I actually was more interested in solving mysteries. It's almost like solving problems that we spoke about for Caltech classes or Caltech exams. I wanted to solve the medical mysteries that persisted until then, and persisted until today. I know you haven't gotten there yet, but that's why I jumped on HIV, because that was an obvious medical mystery that we were seeing for the very first time. ZIERLER: What were some of the big questions in virology and immunology from your perspective in medical school? What was the frontier of knowledge at that point? HO: I think one aspect that really started to take root in me as I was doing my medical school training, as well as subsequent training, was the episodic outbreaks of infectious diseases. Initially, they were all mysterious. What colored my whole experience was, for example, Legionnaires' disease. These people—Legionnaires'—congregated in Philadelphia at a convention, and X number of them came down with pneumonia, all more or less at the same time. It was an outbreak. The CDC jumped into action trying to solve that mystery. It's like a detective story. Yes, over time, they did solve it, and it was a new bacterium, now known as Legionella pneumophila. That, for example, stuck with me, and it was a really good case study of a medical mystery that actually puzzled the world and then, with good detective work, it was figured out, and a new organism was discovered. You could say, okay, Lyme disease. That also popped up around the same time period. People had rashes, and have arthritis, coming up episodically, and due to a tick bite, or many cases following a tick bite. What's going on? That was not known until the new spirochetal bacterium was discovered. One medical mystery at that same time, which wasn't solved until later, was what we used to call non-A, non-B hepatitis. These people, it was clear that it was a transmissible disease. Drug addicts were getting it. Blood transfusion recipients were getting it. So it's in the blood, but we can never identify it. But it's not A, it's not B. Today, we call it C, but that was discovered—we still cannot grow that virus in the lab—but using molecular techniques, that was figured out later. That was a medical mystery to me, and that actually formed a very strong foundation for me to want to pursue these mysteries that turned out to be infectious diseases. I also have to tell you just some years prior to that, even hepatitis B was just being discovered, and that is also a virus we cannot grow. A Nobel Prize was awarded for the discovery of the Australian antigen. That is the hepatitis B proteins, so we had a marker, we had a handle on the virus, even though we cannot grow the virus. Then of course seeing how then that information led to the development of a hepatitis B vaccine, and that allowed people to prevent that infection, and then consequently, years later, shown to prevent liver cancer, for example. So infections couple with cancer, exemplified by hepatitis B, exemplified by herpes simplex with cervical cancer for women. Those linkages also formed a very important impression in my mind. ZIERLER: What about the role of genetics versus environmental factors, diseases that you get that were passed down to you, versus diseases that you get because of things that you're exposed to? What kind of education or training did you get in that regard during medical school? HO: Not a lot, but the classic one is sickle trait. Why would sickle trait be selected when it could lead to inheriting two sickle genes that result in such devastation for the child? But it turns out if you're so-called heterozygous, so you only have one bad copy of the gene, you're actually somewhat protected from certain forms of malaria, which is so common in sub-Saharan Africa. It's a clear example of genetics affecting a very important infectious disease. That one stood out. Of course now we know there are many genes, particularly genes that involve the immune system, that affect clinical outcomes differently. ZIERLER: After you had completed all of the required courses, what opportunities were there at Harvard for specialization within medical school, either in a laboratory setting or in a clinical setting? HO: In medical school, there wasn't much, although I failed to mention that prior to medical school, I joined an MIT lab for several months. This is in between graduation and start of medical school. I worked in an antibody lab, and that formed a very strong foundation for me, because I still work on antibodies to a large extent. That was a lab led by Herman Eisen, who is a distinguished immunologist, a leading figure in antibody function and structure. ZIERLER: Did you keep up that relationship during medical school? HO: A little bit. But amazingly, decades later, Herman Eisen and I would communicate by email and by phone on topics of mutual interest. He's several decades my senior, but I was able to make a full circle with him and reconnect, mostly on HIV antibody issues. ZIERLER: What were some of the big questions in his lab and in antibody research in general at that point? HO: A lot of antibody structure, and understanding which portions of the antibodies are important for recognizing the target. So, structure and function of antibodies. And how antibodies were made in the body through gene recombinations, that aspect, which is very exciting, was not known, back then. It took another MIT professor, Susumu Tonegawa, to figure that out, some years later, and of course he won the Nobel Prize for that. ZIERLER: At what point in medical school do you start thinking about next stages, either residency or career moves? How does that work? HO: I think you start thinking about that once you finish your basic courses and you're going through your clinical rotations. The major rotations are, for example, internal medicine, surgery, obstetrics, gynecology, pediatrics, and so on. Typical of any medical student, you get interested in whatever you're rotating, so your interests evolve through that third year. By fourth year, you are forced to begin to narrow down which area you want to go to. For those who have a research career in mind, you tend to go into internal medicine first, because that's more of an intellectual discipline, where you're trying to understand a problem, and get at the root of the medical problem. Or, you could go into pathology. That's another area where academic medicine excels. You wouldn't want to be spending five, six hours a day in a surgical suite, although there are a number of people who pursue research from that track. But I would say a large, large majority come from internal medicine and pathology. I gravitated toward internal medicine, and still not sure which area I would pursue. I was tossing around the idea of infectious diseases, because I had by then a sneaky suspicion some of the mysterious illnesses were due to infections that we still had not uncovered. One classic example is peptic ulcers. We used to think it's too much acid, years back, but it's due to a bacterial infection, campylobacter. Somebody from Australia won the Nobel Prize for that discovery. I was tossing around cardiology versus infectious diseases by the time I was getting into medical training. ZIERLER: Just anecdotally, among your classmates, how unique were you in terms of having aspirations in a research career, and not a clinical career? HO: It's not unique. I would say about 20% or 25% of the class had such aspirations at an institution like Harvard. That may be skewing high because it's Harvard. If you had gone to, say, a state medical school in the middle of the country, that proportion would be much lower, I suspect. ZIERLER: Did you have any opportunity to interface with patients at all during medical school? HO: Oh, sure, during the third and fourth year, when you do the rotations, you're doing that in the hospitals, interacting with patients, although supervised by interns, residents, and attending physicians. Patient interactions begin in the third year. Nowadays, they begin much earlier, but I'm talking about my experience. ZIERLER: Communicating with patients, literally putting a human face to the conditions that you were thinking about, in what ways was that useful in your intellectual development? HO: You get to appreciate clinical problems. You hear it from the patients. You have that raw understanding of what conditions really mean to a particular individual. Then you have to interact with patients, so you learn those communication skills. You learn to be empathetic. You learn to convey good news as well as bad news. Then when you take it back to the discussion, then all of a sudden you're more focused on the problem and how to solve it, or how to diagnose it. It's really a very interesting experience that you live through for several years. Actually, it really helps to get a deep understanding of the disease, and that's why for some conditions, it's really hard for straight PhDs to do medical research, unless they have a pretty good grasp of that. They can learn that along the way without an MD degree, but having a full clinical background is really very, very helpful in addressing clinical research questions. ZIERLER: When you graduated from medical school, what were the opportunities available to you at that point? What did you want to do next? HO: I chose to train in internal medicine as a steppingstone to an academic medicine career. As I said, internal medicine with the idea of ultimately going into infections or cardiovascular diseases. At that time, I was interested in infection—that part is clear—but the cardiovascular diseases, there was a lot of excitement going on in terms of understanding lipid metabolism and cholesterol and how they may lead to atherosclerosis and huge clinical problems that required new solutions. ZIERLER: What were the residency programs at that point that were considered at the cutting edge of internal medicine and were doing the kinds of things that you wanted to get exposure to? HO: There were probably a couple dozen programs throughout the U.S. that are considered top echelon, and you could get good training at any of them. They're all at academic medical centers in the big cities—Boston, New York, Baltimore, D.C., Saint Louis, Chicago, San Francisco, L.A., Seattle. You hope to land in one of those big programs and get good clinical training, and also get some exposure to cutting-edge research that's addressing unsolved medical problems. ZIERLER: For you, UCLA was also an opportunity to get back home to some degree? HO: Yes, and to get away from the winters. [laughs] ZIERLER: Tell me about getting to UCLA. Obviously it's a much bigger place than Caltech. What was it like there when you first arrived? HO: Well, you arrive as medical interns who, while you have gone to medical school and you now have an MD degree and you're allowed to wear the white coats and walk around and call yourself a doctor, you still are in training, and you're the lowest physicians in the totem pole. I think it's probably the scariest period for a doctor, because in medical school, you know you have supervision, you could always lean on somebody. But once you're on your own, even though you still have people who supervise, they're giving you a fair amount of latitude. That responsibility felt very heavy, at least in the beginning, until you settle in. That settling period could be a few weeks to a few months, and for some, a few years. It's a pretty frightening period for a physician. ZIERLER: What was your first project or rotation that you were on? HO: Believe it or not, I got thrown into the ICU as my first rotation. ZIERLER: Wow. HO: It was the cardiac intensive care unit. It's every three nights. Every third night, you're not getting much sleep, so that's exhausting. Then you're taking care of the sickest patients with cardiac problems. You see many die. But you appreciate what good medical care can do, also. You see people who basically have died, and you resurrect them, and you get them back, out of the hospital and back to life. That was like being thrown into the deep end of the pool and forced to learn how to swim on the spot. ZIERLER: In that environment, what are you learning from the nurses, and what are you learning from the attending? HO: You learn from everybody. Even though you can write the orders for the nurses and they have to execute your orders, most of the nurses have been there for ten-plus years, so they know what to do. You learn from everybody, including the nurses. Obviously around discussing with the attending physicians and senior residents, you learn from those people as well. You pick up very quickly. Within weeks, you could speak the language. You learn how a hospital functions, how to order things, how to run to the right places to look for x-rays and what have you. You learn some of the basic procedures very quickly so you can physically carry out certain things like putting in lines for patients, and putting in certain catheters. It's a very, very steep learning curve for the first six months. ZIERLER: What was your rotation after ICU cardiology? HO: Then the medical wards for several months. There, you see many different diseases, from acute ones to referral cases to terminal cancer. Naturally, I gravitated toward those diseases that had unknown causes. ZIERLER: Such as what? HO: Like, for example, a patient comes in with three months of fever, what we call fever of unknown origin. What's going on? Is that an infection that we haven't uncovered? Is that a rheumatologic condition that we haven't diagnosed? Or is it something else, some genetic disease? Depending on the age of the patient, obviously. Those are the fascinating cases. ZIERLER: Were there mentors during your residency that you really learned from their approach to the research and to working with patients? HO: There always are mentors, in the cardiac ICU or the medical ICU, or on the medical wards. Especially in the first couple years, you just pick up nuggets or what we call clinical pearls, from various attending physicians as well as peers. It just comes in random forms. It's not as systematic as class learning. ZIERLER: What opportunities, if any, did you have for laboratory research during your residency? HO: None. Especially in those days, you're just scheduled from one rotation to another. There's hardly any time to sleep [laughs], not to mention research. ZIERLER: Basically internal medicine gives you the widest possible angle to every malady that humans face when they get to a hospital. HO: Right. ZIERLER: What was valuable to you, to have such a wide perspective on all of these issues? HO: It is really to understand a wide range of diseases, and some of the underlying pathology or the mechanism, what we call the pathogenesis—how certain diseases come about. Obviously some are known, and some are unknown. And getting a really good appreciation of what can go wrong in a given body, or what organisms are out there that could invade us and cause problems, or how our immune system could attack our own body, due to some signal that triggered it, which we to this day still don't understand fully. Those are just a few of many examples of what you learn to appreciate through clinical training. Then you decide which sort of problems interest you the most. For people who eventually turn to infectious diseases, it's because of the long history that many of them turn out to be treatable. It wasn't so until the antibiotic era, of course, after Fleming, and so on, but at least by the time I was at that stage of my career, many infections were treatable. Many bacterial infections were treatable. A number of fungal infections, a number of parasitic infections were treatable with drugs. It's a bit unlike cancer, most of which were untreatable at the time, and many are still untreatable today. ZIERLER: The last topic we'll talk about for today's discussion—we touched on it briefly in our initial conversation, but now that we're in the narrative, we can go into it in a little more detail—do you have a specific memory of when people started to come into the hospital in Los Angeles with a new illness that would later be identified as an HIV infection leading to AIDS? Do you have a specific memory of that? HO: Yes, very clearly. Because this was in my senior residency year so it would be late 1980. Remember, 1981 was the year that AIDS became officially recognized, so this would be a period before that. It's late 1980; a gay man comes into the hospital with bilateral pneumonia. ZIERLER: What does that mean, bilateral? HO: Both lungs, infiltrated with something causing pneumonia, having a hard time breathing. On x-ray, you see haziness on both lungs. That was already unusual in a young person. Then obviously no obvious diagnosis was made until a bronchoscopy was performed. You put the tube down, you wash the lung, and you take the fluid out, and from those washings, it was determined that that patient had a pneumocystis carinii infection. That's an infection you only see in people whose immune system had been destroyed. ZIERLER: And that was known already, that this was unique in terms of what it was doing? HO: Prior to that, pneumocystis carinii pneumonia was seen in patients on chemotherapy and transplant. This first case had no such medical history. That was extremely unusual. Then he also had seizures. When you do a CT scan of the brain, there were holes in the brain. Of course we had to find out what was the cause, and then you do a a small-opening brain biopsy and it turns out to be a parasite named toxoplasma. That too is an infection that you only see in cancer patients or transplant patients. So even one case, that raises suspicion that does this patient have some underlying immune deficiency. But this person had lived a life of 20—I forget the age—20, 30 years—without any problem, so it's not a genetic immune deficiency. ZIERLER: When did it start to be apparent—where were the patterns that you recognized that this illness, before it was even identified as AIDS, was harming gay men in particular? HO: You asked the first case, so that's the first case. Then he was treated, he went home, and he died within weeks after discharge. ZIERLER: And you knew he was gay? How did that become known? You asked him? HO: Oh, yes. It's common that we take a sexual history as part of a complete medical history. What was striking—and this will be very important—is that he had a number of what we call gay-related infections. He had syphilis. He had what we called gay bowel disease. It's essentially gonorrhea of the rectum or chlamydia of the rectum. So even from the first case, we knew that there was something wrong with the immune system, and that this person was a gay man who had a number of infections. That automatically—it doesn't take much to think, "Well, could what's going on here be a new infection?" But that's one case. Then a couple weeks later, another gay man came into the hospital. Now, not with exactly the same syndrome, but certainly with pneumocystis pneumonia, and then had retinal infection by a virus called CMV. That, you also see in transplant patients. Now you have two cases. Then a few weeks later, there was another one. In this way, five cases were seen in late 1980 and early 1981. Those five cases, I happened to be there. I was not in charge. I was a resident, so I wasn't the intern, but I was a senior resident. By then, I had enough medical knowledge to know that there's something wrong here. All of them were gay men with a number of gay-related infections, and they all had a similar syndrome that suggested their immune system was impaired. They were coming in, one after another, not rapidly, but over a few months' time. There was a common thread. They were all gay, they were all young men, and they had no prior history, except for the various sexually transmitted diseases. And if you take a careful medical history, they had lots of partners, sometimes into the hundreds, so infectious transmissible disease had to be on the list. But then if you look at the textbook, is there a transmissible disease that knocked out the immune system? No. Even to a nascent physician, it didn't take much to say, "Could this be something new?" That's the mystery part again. To me, I was just tracking these cases even if they are not mine. I would find out if there were more such cases coming into the hospital on the nights that I'm not on. Then, fortuitously, by June of 1981, when I became chief resident, then I hear about every single case admitted to the medical service, because the interns and residents had to report to me all the cases. By then, the first five cases have been summarized and reported to the CDC. The CDC had been noting that there had been a dramatic increase in requests for pentamidine. Pentamidine is used to treat pneumocystis pneumonia. So CDC made the connection, these five cases with the request nationwide for pentamidine. That's a controlled drug at the time, so CDC would hear about every case of pneumocystis that way. ZIERLER: David, do you have a sense that, going back to that very first patient, was this patient zero or close to it? In other words, was this happening earlier than anywhere else except perhaps maybe New York? HO: Yes, I'm sure it was happening in New York and San Francisco, and of course after the first report from L.A., New York and San Francisco, within a few weeks, had similar reports, all through what's called the MMWR, the Morbidity and Mortality Weekly Reports, from the CDC. The finding from UCLA—this is not my finding—from the immunology lab, that also provided a common thread for all of them, is by 1981, there was a new test that measured certain type of T cell counts, particularly CD4 T cells. That number was found to be low for all of them. That really unified this cluster of patients—all gay men, all seemingly immunodeficient, and documented low CD4 lymphocyte count, and then having a multitude of infections that are consistent with having severe immunodeficiency. Then all of them had a normal medical history prior to that, so it was not an inborn immunodeficiency disorder. It was acquired. ZIERLER: For my last question, I'll just note that for you, who was interested in the mysteries of infectious diseases, boy, did you find one. My question is, with all of your appreciation for the value of being in a clinical environment, and the human dimension here, which is it's scary enough to have a life-threatening illness but it has to be even scarier when the medical professionals have no idea what it is, did that plant a seed in you that looking back you recognize, that was the additional motivation that would compel you to spend your career, your life working on this? HO: As you can tell, I was drawn to find out what was going on with these few patients, and I have to emphasize few. At that point in time, I was leaning toward cardiology, even though I had these interests in infections. Cardiology is a very dynamic discipline, and I had many mentors who said, "Why would you want to give that up to focus on this esoteric problem?" But I have to say, the mystery part really captured me, and I just pursued it. I just knew it was an important scientific problem. You have a new transmissible disease, a seemingly transmissible disease, that destroyed the immune system. Whether it's esoteric or not, it's an important scientific question, of what's doing that. That's why I went into it. I was all in, even before I joined the lab, from the clinical side, and I spent a year collecting such cases, from middle of 1981 to middle of 1982. Then I returned to Harvard and went into infectious diseases, and went into the lab to study this problem. ZIERLER: On that note, we'll pick up for next time where you get further and further into this mystery. [End of Recording] ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Monday, February 7th, 2022. I'm delighted to be back with Dr. David Ho. David, as always, it's good to be with you again. HO: Good to see you again. ZIERLER: What I'd like to do today is before we go back to those very early days of the HIV pandemic, I wonder if we could superimpose what you were seeing in real time then with all that we have learned about HIV and your contributions to it in the meantime. Just as a basic primer, when someone is infected with HIV, what are the biological processes that lead to symptoms, illness, and if left untreated, death? HO: If you're asking about what we know today, I could give you that. HIV gets into a person, usually via sex, occasionally via blood transfusions and such. The virus gets into a particular cell that we call CD4 lymphocytes. These cells are a very important player in our immune system, orchestrating a number of different critical functions. What we have learned over the years is that the virus infects that cell and primarily that cell, very few other cells, and just from the outset starts to replicate in those cells. Initially, in the first say two to four weeks of infection, there's a burst of virus that typically results in a flulike illness. Most people simply attribute it to another viral infection. Then that illness will self-resolve, and the virus is brought under control at varying levels, depending on the person. Then that person is asymptomatic and goes on for many years, if untested, not knowing about the infection status. I said earlier at varying levels—if the virus remains at a higher level, the person will develop AIDS faster. If it's at a lower level, it will develop slower. What determines that balance is a reflection of the immune response, as well as the characteristics of the particular infecting strain. But typically it would take somewhere around ten years for a person to go from infection to development of AIDS. That's because during this prolonged period, while the person is essentially asymptomatic, the virus is cranking away, and slowly, slowly depleting this important cell population that is so vital to coordinating many important immune functions. That's what we know. About 99% of the time, if left untreated, and if followed long enough, the infected person will die from AIDS. It's an extremely lethal disease if untreated. But it's also very insidious. It takes many, many years for the disease itself to manifest, unless you're doing testing. ZIERLER: What exactly kills a person when they're left untreated? What is that mechanism? HO: Typically it's not HIV itself. Most of the time, the CD4 cell number drops below a critical level. Then that person is prone to develop many other infections, and many of them are infections that normally do not do much harm to a healthy person, but when the immune system is depleted to an extent, then they would develop bizarre infections. Last time, we talked about pneumocystis, which is only seen in cancer or transplant patients, and now HIV patients. That would be common. Normal people don't get that kind of infection. They're what we call opportunistic infections, and you can name a couple dozen pathogens that would infect the lung, the brain, the gut, the eye, and many other organ systems, simply because they're opportunistic. They only matter when the immune system is down. ZIERLER: Just theoretically, if somebody lived in a hyper sterile environment—the ultimate lockdown with masks and all the rest—could somebody live with HIV a healthy life if they're not being exposed to illnesses for their weakened immune system? HO: Well, unless they lived in a bubble from childhood—from infancy, in fact—because many of the pathogens that affect HIV patients are ones that are already in the person's body. For example, a cytomegalovirus infection, most people have acquired that during childhood. When the immune system is down, that comes back, and that could cause retinal destruction, it could cause hepatitis, it could cause gastrointestinal problems, and could kill. Shingles, for example, could appear, and it could be disseminated, and that's because of childhood chicken pox. So there are a lot of these things that are already in the system that you can't do anything about, and they are also ubiquitous in the environment. And yes, indeed, HIV if you let it continue, could also cause the person to lose weight and also could do a lot of harm, but that typically comes only after the opportunistic infections have already occurred. ZIERLER: Let's go back to the early days in Los Angeles. Was your sense then in retrospect that if this virus can incubate and a person could be asymptomatic for many years, that the initial patients that were coming to you had been infected not weeks or months before, but even years prior to interacting with you first? HO: That is absolutely correct. They were infected many years before. Of course, these could be the ones that developed disease first. I mentioned that high levels of virus would manifest itself earlier, so we probably were seeing people who were infected for three, four, five years, rather than ten years, at that time point, because they came in early in the process. There's always a bell-shaped curve in terms of distribution of when one would develop disease. Those people who came in, in late 1980, 1981, they're the earlier cases, and they were undoubtedly infected a number of years before. Probably by the 1970s, the virus was already in the country, probably spreading undetected. ZIERLER: Was there initial concern about transmissibility and the way that healthcare practitioners might need to take special precautions? In other words, were people talking about masks or extra layers of protection simply because it was not understood how this transferred from one person to another? HO: Yes, I would say in the very beginning, the first six months or so of recognition of this syndrome, there was a lot of fear, and even fear among healthcare workers and others who were involved in the care of these individuals. Since it was so mysterious, we didn't know very much about it. However, for those who looked into the disease more deeply, it was clearly a sexually transmitted disease, at that point. Now, by a number of months after the initial detection, there were some cases that were not fitting in very well, in particular Haitians, who were not gay men. I saw one such case in 1981, for example. They didn't fit the bill, and yet had—and so there was some concern that there may be other routes of transmission. Of course in retrospect, we understand the Haitian connection, but at that time, we didn't know whether the Haitians were acquiring it by sex or not. Then, again, some months later, there were cases of hemophiliacs and blood transfusion recipients. That says it's sexually transmitted and bloodborne. So six, nine months into the early visible part of the epidemic or pandemic, it was believed by the experts who had been looking at this that it's probably not casually transmitted, and more likely blood and sex related. ZIERLER: I'm curious, before you and your colleagues reached the conclusion that it was not casually transmitted but it was sexually transmitted, if you were aware of concerns earlier in the 1970s that led to the creation of, for example, the Asilomar Conference that David Baltimore and others led, stemming from the concern that with the recombinant DNA revolution, all kinds of scary things could happen in a laboratory research environment. I'm curious if you thought about any possible connection in the very early days between this new syndrome and something that might have come out of a lab, by accident. HO: It didn't cross my mind. What crossed my mind was, "This looks like a new pathogen." That in itself was already enough of a mystery. As to its source, obviously in the beginning, we had no idea. We just knew that it was being transmitted among gay men, and then the blood recipients or hemophiliacs who received blood products. We knew gay men were a major donor population for blood donation. Obviously we didn't test for that at the time, so that explained why we were seeing the infections in certain individuals. But in terms of the source, that remained mysterious for a long, long time. But it didn't cross my mind that this was engineered or leaked or anything like that, from a laboratory. ZIERLER: Once it became clear that this was primarily a health crisis in the gay community, were you involved at all in campaigns to raise public awareness, outreach with community leaders, that this was something that these people should be concerned about? HO: I was not that involved in that aspect, because quite frankly, I was a pretty junior scientist, and I had things to do in the lab, things to do in the clinic. I pretty much focused on what I needed to do. Now of course I followed with great interest what was going on in society. I read about the fear within the gay community and how mistreated—and I could personally witness how mistreated the patients were. They were shunned by healthcare workers. They were shunned by families and friends, because people had a lot of fear about this new disease, and it was clear that these young men were dying very quickly. Everyone was afraid to catch this. You asked about masks and so on; of course until it became clear that this was a sex- and blood-borne disease, all the precautions were taken. The healthcare workers were gowning up, wearing masks. I should say, many of the patients actually had TB, which is also an opportunistic infection, and so masking was mostly appropriate for that, but in retrospect inappropriate for HIV itself. ZIERLER: What therapies were available? What were you thinking of minimally to make the patients as comfortable as possible if not even to search for a cure? How could you prolong their lives to the greatest extent possible at that time? HO: Fortunately, many of what I call opportunistic infections were treatable. Last time, we talked about the use of a drug called pentamidine to treat pneumocystis pneumonia, and there are other drugs to treat that pneumonia as well. So we could take care of the acute problem that resulted from the immunodeficiency, but we could not treat the underlying disease process. I think all of us knew that, and all of us knew that we can't treat that until we find the cause, and the cause was essentially unknown until 1983, 1984, that period, when a retrovirus was first identified to be linked to this disease in 1983. By 1984, it was pretty certain that that retrovirus was the actual cause. ZIERLER: In the senior year in your residency, you mentioned last time you were in the lab at UCLA. You were working on unraveling this mystery. Let's talk a little bit about that. What's the biggest mystery? What is the fundamental thing you're trying to figure out? And then how did the questions get more specific and targeted from there? HO: Let me correct the record a little bit. Yes, in my senior year and senior residency year and chief residency year, I was at UCLA, but I was doing mostly clinical work. I did not get to the lab until 1982, in Boston, and that's where I began to focus in the lab on this problem. ZIERLER: Now let's go to the decision-making. You return to Boston in 1982. Where? Where are you going first? HO: I went straight into an infectious disease fellowship at Massachusetts General Hospital and Harvard Medical School, and I worked in the laboratory of Martin Hirsch. Marty is a virologist. He worked on cytomegalovirus, and herpes simplex virus, and others. Obviously this arrangement was made about a year prior to my going. AIDS was already on the radar, and he, like me, was quite interested in this new disease. Because of that mutual interest, I was the first one he put on the project to study these patients. ZIERLER: Do you have a clear memory of when the terms "HIV" and "AIDS" came into use? HO: No. AIDS went by many other names, but sort of a nomenclature committee, later, about a year into the disease recognition, AIDS was named. Prior to that, it had many other names and some rather derogatory. GRID was a common one—"Gay-Related Immune Deficiency." Of course that turned out to be largely incorrect, as the pandemic exploded throughout the world. It's certainly not largely gay-related, except in the U.S. and Western European countries. ZIERLER: To give a sense, you said that by this point, when you got back to Boston, this illness, this syndrome, was already on the radar. But how much was it, really? In other words, were there many places you could have gone to, to pursue this interest, or was Hirsch and that lab really pioneers in this field? HO: No, they were pioneers in virology, but in a different discipline. At that point, we didn't know what virus or what agent was causing this. Of course there are many laboratories throughout the world doing virology, some working on herpes viruses, others working on influenza viruses, and others working on retroviruses that up to that point largely were not associated with human disease. When you don't know what category the pathogen fits into, you cannot pick a proper lab, so you go to a good virology lab, and hopefully that will be the base and the foundation for the work. ZIERLER: How did you first connect with Hirsch? Were you just generally an admirer of his work? HO: Many reasons. One is I wanted to do my infectious disease training in a good place, and the program at Massachusetts General Hospital is one of the top in the country. That formed a big reason for wanting to go to that institution. Within that institution, Marty was the leading virologist. During the interview process, I talked to him, his colleagues, and others in the lab, and I felt that was a great place for me. Similarly, I almost went to a program at the Fred Hutchinson Cancer Research Center in Seattle. That also had a strong program in infectious diseases, and a number of people were involved in virology there. ZIERLER: Did Hirsch have direct contact or did he interface at all with AIDS patients himself? HO: Yes, yes. He's a physician-scientist, so he has both laboratory and clinical background. ZIERLER: When you get there, what exactly is the project, and who was funding it? I think that's important to see who's putting effort into supporting this research in this early period. HO: Hirsch did not have funding for AIDS, because it's new. Very few people had. But he had funding for his virology. It's sort of like robbing Peter to pay Paul, here. Basically we just used whatever resources he had at his disposal, and we started to look at patients. In particular, one aspect of the AIDS complication was a problem which we called Kaposi's sarcoma. Kaposi's sarcoma has been long recognized in Africa as a skin cancer, with black, dark spots all over, and sometimes in the mouth and the gastrointestinal tract for severe cases. In the first few cases of AIDS, we already knew some of them had Kaposi's sarcoma also. There was always an impression that Kaposi's sarcoma was transmissible, and therefore had a viral cause, perhaps. In fact, there was quite a bit of literature to suggest that it may be a virus, and it may be in the herpes family. Since Hirsch's lab was focused on the herpes family of viruses, the first problem I focused on was Kaposi's sarcoma that was being seen in the AIDS patients, to see if there's a cause for the Kaposi's sarcoma seen with AIDS, because that would link the AIDS problem to the expertise of the lab. Years later—this is not my discovery—years later, scientists at Columbia actually found that it's due to a herpes virus, which was termed herpes-8. This was the eighth herpes virus discovered in the field. So that suspicion turned out to be true. But because I then was working on samples coming from these patients, I took a great interest in what was causing the underlying condition, rather than what was causing Kaposi's sarcoma. I started to take samples to look for a virus. Of course we didn't make that discovery, right? The scientists at Pasteur and scientists at NIH in 1983 and 1984 really identified the virus and went on to show that definitely this new retrovirus was the cause. My work was behind. Those two groups were first, and another group at UC San Francisco also, within a month or two, reported the isolation of the virus, and our group was the fourth. We were beaten. But it taught me a very important lesson, that you could be working hard and making the same discovery, but even if you are a week late, your work would be undervalued a great deal, because it's already known to other people through other endeavors. ZIERLER: Did you feel like you were in a race? Was it a friendly competition? Were you aware of what was happening in these other research groups? HO: Oh, yes. A lot of virology labs throughout the world were looking at this, so we knew. But if you look back, the people who discovered this virus were retrovirology labs. That makes sense. It was the retrovirology lab at the Pasteur Institute, the retrovirology lab at the NIH. They had all the methodologies already, and no surprise—and the UCSF lab was a retrovirology lab. We were the only non-retrovirology lab to quickly—and we caught up very quickly. Our publication was only a couple months later. Of course by then people already knew what the cause was, and we sort of just added to the record. ZIERLER: The samples you were studying, what were they samples of, and what were you seeing? HO: We were studying blood samples, of course. We know the virus is in the blood based on the clinical information. We were studying genital fluids, semen and other genital secretions. We know the virus has to be there, based on the clinical information. We were putting it on cells to see if something would grow out that we could identify as a new agent. We also know that the virus seems to cause a destruction of these CD4 T cells, so the natural thing to do was to try to grow an agent using CD4 T cells that were derived from blood donors, normal donors. That's exactly what the Pasteur scientists did, NIH scientists, and the USCF, and we were doing the same thing, except we didn't have all the tools that they already had in the lab. For example, David Baltimore's Nobel-winning discovery of reverse transcriptase, those assays were up and running in retrovirology labs, but not in our herpes lab. I had to sort of reinvent that in order to do what the other labs did. The NIH lab had maybe 50 to 100 people, the Pasteur Lab had probably a group of 20 people, and I was doing this by myself. ZIERLER: [laughs] HO: With one technician. So there was no competition; they of course were way ahead. But once the virus was discovered, I did a lot of things that a physician-scientist would do. I could quickly show, for example, that the illness that I talked about, at the very beginning of infection, that was due to HIV. The work I did was the first to show that HIV acute infection could cause a transient illness, and that's the first sign, and then the people become asymptomatic. Then the work I did, published in the same year as the NIH papers in 1984, showed that the virus is carried by asymptomatic people, so there's a carrier state. That's of course very important for transmission. The person is carrying the virus and could pass the virus on, even though he was not sick. At the same time, we showed that the virus is present in semen. That makes all the sense, because of how this disease is transmitted. Then, because I was not only doing the lab work but I was seeing these cases in the clinical and in the hospital, there were a lot of neurological problems seen in the AIDS patient. Some of them are due to the opportunistic infections, but even absent that, there was a lot of neurological deterioration, and it was clear that there was more than just immunodeficiency. I think our group again was the first to show that these neurological problems were a consequence of HIV infection. From the postmortem cases, we could find the virus in the brain, in the spinal cord, in the spinal fluid, and show that late in disease, the virus would go on to destroy the neurological system as well. That's because the virus infects another second cell type called macrophages, and macrophages could move into the brain and turn into what's called microglial cells, and somehow indirectly cause the damage to neural cells. How that occurs is still unknown today, believe it or not, after all this time. ZIERLER: In that timeframe—1983, 1984—how well-developed is the subfield of retrovirology? HO: Retrovirology was of great interest to many basic virologists who were trying to understand what retroviruses do in animals. In fact, retrovirology was of great interest because many of these animal infections due to retroviruses result in cancer. No doubt, that's why David Baltimore was working on retroviruses and reverse transcription. There are many retroviruses that cause leukemia, lymphoma, and other cancers in various animal species but not humans. But, by the time AIDS appeared, almost concurrently, it was being discovered that—and this came out of the NIH—that there's a very rare lymphoma cancer in humans that was occurring in places like Japan and the Caribbean. Japanese scientists and the NIH team that I spoke about, under Bob Gallo, discovered a human retrovirus called HTLV-1 that was associated with that human lymphoma, which was T cell lymphoma. Interestingly, it also infected T cells and caused T cell lymphoma. I think that was the beginning of human retrovirology. Prior to that, there were no retroviruses causing human conditions. ZIERLER: You mentioned earlier that your competitors at Pasteur, UCSF, and elsewhere, there was an unfair advantage methodologically. Let's start first with the instrumentation. What did those labs have that you were not working with? HO: I think most importantly, a routine assay for retroviruses was to see if something is spreading in your tissue culture, and then detect the presence of reverse transcriptase activity. That was the key. That's a biochemical assay that Baltimore and Temin developed in the 1970s. That's a routine assay in a retrovirology lab, but not one in the herpes laboratory. So I had to spend quite a bit of time—and I also did not have a lot of biochemistry background. I knew my knowledge in biochemistry, but in terms of hands-on experience, I wasn't all that savvy with such assays, so it took a while to get that going, and that was the key. Also, the fact that the other teams have lots of people, and I was a junior postdoctoral fellow, basically, working on this, whereas the rest of the lab was working on herpes viruses. What would have been really useful was the reverse transcriptase assay, and electron microscopy that would be readily available in a place like the Gallo Lab or the Pasteur Lab. ZIERLER: What about intellectually? What kinds of questions were people in retrovirus labs thinking about that might not have even occurred to you at that point? HO: I think probably not that much more. I think it's mostly methodology and familiarity with retroviruses and how the genes are organized. Obviously they had more in-depth knowledge about all of those things. But I think it was mostly the availability of the tools. We all read the literature, and by then we knew that there was one human retrovirus, and that happened to infect T cells. Coming back to the nomenclature question you asked earlier, this is why initially HIV was called HTLV-III by the NIH group. That name stuck for a number of years, even though HTLV-III, or HIV today, is not that closely related to HTLV-I and HTLV-II. HTLV-I caused the adult T cell leukemia that I mentioned, and some years later, HTLV-II was discovered, and that caused another kind of—we call it hairy T cell leukemia. Even those of us who did not work on retrovirology could make the connection—"Hey, there's already a human retrovirus that infects T cells, so this disease, if it's a retrovirus, we should look at T cells." That didn't take much to connect the dots. ZIERLER: What did the actual discovery look like? Was it a eureka moment? What was identified that made this clear, what this syndrome was? HO: I'll tell you what the Pasteur group first reported. They first reported in a few cases the detection of the reverse transcriptase activity in their cultures. Then they showed a virus particle on their electron microscopy. That's pretty much it, and it was not convincing. In fact, if you look back at the electron micrograph from that publication, in retrospect it doesn't even look like HIV. But, they were the first to detect the reverse transcriptase activity, and they reported that. That's why the Nobel Prize in the AIDS discovery was awarded to the Pasteur people, and not to Bob Gallo at NIH, and not to others that came later. What the Gallo lab did was to detect the retrovirus in convincing ways, in ways that the Pasteur group had not done. To grow the virus, and to show the reverse transcriptase in robust fashion, and that it's passed on and on, and they isolated not just one but many such viruses from dozens of cases. Then using the virus that's then isolated to develop a blood test to show people who have AIDS almost always have antibodies to the virus, and those who are not, and not just healthy carriers but the healthy individual, normal donors, don't have antibodies to this virus. They went on to show in a very convincing way—that's why I said the discovery was really—there was not a eureka moment in the sense that the Pasteur group provided a hint, which was fully developed by the Gallo group. I'm sure that involved an army, and they published four papers simultaneously in Science. In fact, you could tell about 100 people worked on that. ZIERLER: The people who published before you, given that your paper came out four months later, were you influenced by their research? Were you confirming what they saw? Or were you able to draw new conclusions based on what your colleagues elsewhere were finding? HO: I think I was mostly confirming. I think certainly by the time that—the Pasteur group was, like I said, not convincing, but provided a hint, a clue, and certainly motivated me and others to look even harder at retroviruses. By the time the Gallo/NIH papers came out, we pretty much had something on a few cases that would confirm their results, independently generated, but we were clearly months behind their work. They convinced the world already. For us, yes, we published what we had, but we also knew there were plenty of other unanswered questions that we could address. Once the retrovirus was clearly established as the cause, there was a lot of low-hanging fruits to be picked, especially for someone junior like me who also is bridging the clinic and the bench. That's why I told you all those things earlier about the discoveries that we made in the 1984 period, about the acute infection, about neural invasion by the virus, about the carrier state of asymptomatic individuals. All those, we did in short order, and really propelled our lab into the active echelon of folks working on human retroviruses. ZIERLER: Before we proceed to the next steps, what's able to be considered now at this point, let's zoom out to the national level. What's happening in the Reagan administration, at the NIH, at the FDA? What's happening that suggests that there is at least the beginnings of a national response to this crisis? HO: I think I would give a fair amount of credit to CDC, which recently has been criticized for a number of things in COVID, but in retrospect I think CDC did a great job of tracking this new disease, making everyone aware of it, and keeping a head count. They brought a lot of attention to it. Some of the leaders at CDC were leaders in the field. The Reagan administration on the other hand was largely silent. This was a gay disease. You know the conservative nature of that administration. You could say it wasn't until the end of the Reagan era that the administration uttered the words "HIV/AIDS." So yes, NIH responded, and Congress, to some extent, but it did not receive the full blessing of the administration to proceed and treat this like a new epidemic. There are slides that I have had from long ago that show, if you draw a map of the U.S. and show a few dots in 1981, and see how that blossomed over the eight years of the Reagan administration, it's incredible. Explosion of cases. What's going on in society, as we talked about, there was a lot of fear among gay groups, and they were I would say mistreated. People just don't want gay people going to certain public places, in fear of catching something. Stigma and discrimination were big parts of life for the gay population. ZIERLER: It's a counterfactual, of course—there's no way of knowing what could have happened—but is your hunch, if the Reagan administration did not approach this in cultural terms but simply as a matter of public health and put the full resources of the federal government, would the AIDS crisis of the 1980s been much better contained otherwise? HO: There's no doubt we could have done a much better job, nationally speaking. In fact, it was all the way until the Clinton era did the NIH funding take a real jump and a concerted effort was launched. I still would give credit to the NIH leadership for directing a lot of resources to this, but it was obviously diverting funds from other areas into this new field. But there was not a massive infusion of support from the Reagan administration into this area. ZIERLER: Was Anthony Fauci at the center of all of this from the beginning? HO: I don't recall exactly when he became the director of the NIAID, but he certainly was in the middle of all of it. Certainly as the gay activists became organized, he was actually a major target for their critique. ZIERLER: Because he did not do enough in their view? HO: I think they always have to pick somebody. Obviously, as a scientist, I know he was trying his very best with limitations, but they had to pick a number of targets. Of course they protested Reagan and Bush, the first Bush, and the NIH director at the time, and of course Tony Fauci, because much of the funding to support this area would go through Tony's institute. So he was a target. He initially kept a distance, but I think he learned over time that he could actually engage and participate in the conversation, and actually that turned out to be a very nice model for activism engaging the scientific community to move agenda first. That has been the model, and the breast cancer community and many other disease-related communities have adopted that model, and actually together helped push the FDA—for example, if they were promising a drug—to move them along much faster. Many of those new paradigms were developed under HIV/AIDS. ZIERLER: Now let's go back to the moment of discovery and the plan forward. For you, what are those low-hanging fruit? What is there to work on next? HO: Like I said, I was and am a physician-scientist. The research lab do their own thing, and the clinicians do their own thing, but I could bridge the two. That's why I could, for example, think about what's going on in the clinic and bring it back to show that the virus is invading the testes, is invading the central nervous system, and a lot of clinical conditions could be explained by the virology. Then I could go on to show that within the brain, there are these cells that are called microglia, and they are derived from macrophages, and go back to the lab and show that macrophages are infectable. These are all things that we did for the first time and published before others did. In terms of other things, for example, there are lots of things that were already out there as agents to treat other viral diseases, so it was logical to see if we could take some of those and apply it to the new virus. I can remember one of the early papers that I published that got a lot of attention is whether interferons—interferons were being used to treat hepatitis, and they are general antivirals, so we showed that interferons actually could suppress HIV replication. These are things that were almost obvious. You could sit down from day one to write a list of things to do, and these are the most obvious and most easily done. As a young researcher who now has a year or more of experience in the lab doing this, it's a no-brainer to do, and to get the results out to the world. It's almost a bit like what we're going through with COVID now, because it's so new that there are lots of low-hanging fruits for the scientist to pick. ZIERLER: Because of your ability to traverse back and forth between a clinical and a research environment, what advantages did that give you? In what ways were you able to advance the research in general, having your foot in both worlds? HO: I think being a physician would cause you to ask the questions differently. You would ask certain questions from the perspective of a doctor, and that would be quite different from a person who is focused on the virus and then asking the questions coming almost from the other direction. I will just give you another set of examples, which occurred temporally much later. This I would say already takes us to the 1990s. By then, we recognized that there were some individuals who are infected but do very well, the so-called outliers, 1% of them. Why? Now, you would only ask such a question coming from the clinical side, because you are seeing these cases. "Hey doc, I've been infected most likely for ten, 15 years. My CD4 T cells are normal. I'm HIV-positive in my antibody testing. But I'm just fine." When you'd look at their blood, the virus is suppressed. They're not taking any medicine. Some of them are seen in an era when we didn't have any good medicines. So what's going on with the outliers? By studying the outlier from the clinical side, you could get an appreciable understanding of what's going on. It turns out that for them, and we studied these people who are called long-term survivors, and get an understanding that in some cases, the immune system is uniquely capable of suppressing the virus. Now, not everyone could do that, but some of these could, and show that the immune system is actually making a pretty big contribution to keep the virus in check. Let me give you an even more dramatic clinical example. "Hey doc, I am a gay man of 45 years old. I have had 100 partners, many of whom have died of AIDS. We had lots of unprotected sex, and yet I'm not infected." This is another subset of outliers, and what's the reason that they're not infected? It turns out to be genetic. We studied these cases in the 1990s and showed that for some of them—not all of them; for some of them—if you take their CD4 T cells from their blood and put it in the lab and try to infect with HIV, HIV doesn't infect. Up to that point, almost everyone's cells in the lab would be infectable, but these rare individuals, their cells were not infectable. It turns out that they lack the co-receptor molecule, a molecule called CCR5. That discovery was made at our institute, simply from the clinical side, and by saying, "Wait a minute, why aren't these cells infectable, and what's different?" It turns out they are what we call homozygous defective for CCR5, the coreceptor. That discovery was made as CCR5 was being discovered as the coreceptor via another approach, and we showed that that was absent. Now, interestingly, that also helps explain why some individuals do so well with infection. These other individuals who are infected—infected, now; they're not protected—infected, but live quite a long time with HIV without treatment, and it turns out they have one copy of the normal gene and one copy of the defective gene, and that's called a heterozygous state. Having one copy of the defective gene is protective. So some of these questions, not exclusively, but are largely coming from the clinical side. A basic scientist working in the lab would not be asking the same questions. We naturally would occupy a space, a sweet spot, so to speak, that would be good for doing investigation. That's what my career over many decades has largely been focused on. I don't necessarily have to compete with all the numerous strong bench scientists or all the people who are doing clinical trials and such things. I could define my own space and bridge the gap in many different ways. ZIERLER: With your interest in identifying why the outliers were doing well, more generally, were there advances in the field of genetics that were useful for this work? HO: In genetics, huge advances were being made, but up to that point, they were not being applied. It was mostly toward the Human Genome Project, which came to fruition sometime later. Later, once the Human Genome Project was done, a lot of that technology was brought back to the HIV field, to see why some individuals do well and some individuals don't do as well, and in the course of doing that, uncover a number of genetic factors, but the biggest one is still CCR5. The other ones are immune molecules, molecules that differ from person to person but are involved in immune responses. But we already knew from the work done that some individuals have very robust immune responses, and others don't. So yes, the modern genetic methods were brought to bear much later, but only confirming what we already knew. Did not reveal anything new. ZIERLER: Obviously at this juncture, in the mid 1980s, you're operating in a fundamental research environment, just trying to figure all of this out. What was your sense of the broader conversations about upstreaming, as we say in public health? Prevention, public awareness, safe sex. What kinds of conversations were happening along these lines during this timeframe? HO: A lot. I don't want to take any credit for that. That was largely being done by CDC, NIH, and other people, and the media, and I would say I contributed my voice to that. The practices within the gay community changed so much in the first few years of the HIV outbreak. Having numerous partners was modified substantially. Having unprotected sex was drastically altered. The bathhouses were closed. There were a lot of changes going on in society. And the message, and also the calming messages that, "Hey, this is not a respiratory virus. It's not casually transmitted." In fact, we were the first to show that there's actually very little virus in saliva, and whatever virus is there is actually not infectious. There's something in the salivary secretions that inactivated HIV. Even though the particle may be there, it's not infectious. So we contributed what we can to calm people about the lack of casual transmission, so that a lot of the discriminatory practices were off target. If you're not having contact with blood or sexual secretions, you're not at risk. Whenever appropriate, we would help to lend a voice, but much of the public health messages were being done by other people. ZIERLER: At this stage, were pharmaceutical companies starting to think about drugs and therapies? HO: Yes, yes. By about 1984, once the retrovirus was shown to be the cause, the pharmaceutical companies that had been working on antivirals jumped right in. One of them, the leading antiviral company at that time, was Burroughs Wellcome, which has gone through many different partnership and ventures. It is now part of what is called GlaxoSmithKline. Burroughs Wellcome had a lot of stuff on their shelves that they brought into testing. They began that effort in earnest in 1984, and by 1984, 1985—certainly by 1986—they had found a number of compounds that worked in the laboratory and started trials on the first compound called AZT. AZT was shown to be beneficial in patients for a period of about three months, and prolonged life by three months, which was substantial at that time. It was a very significant finding. Then why it stopped working was not known until a little bit later, and that was it developed a drug-resistant virus. ZIERLER: Was the approach of the so-called cocktail therapy, was that embraced from the beginning as the most promising avenue of therapy? HO: No, not at all. AZT was the first to go into people and as I mentioned, was found to be transiently helpful. Other drugs came along. They'd go by various names—ddI, ddC. Interferon was tested. They were all targeting the step of reverse transcription, and they were all taken off the shelf from the cancer effort and from other antiviral efforts. They helped modestly from about 1987 to about 1992. We would call that the dark period of AIDS therapy, where by then, the caseload was heavy, and the death rate was huge, and there was very little that impacted on survival. Yes, a few months here and there, but many clinical trials showed that the benefit was minimal. ZIERLER: What about vaccines? Were people thinking about vaccines from the beginning, and was there a sense, even at the very beginning, that this particular syndrome, HIV, would be so difficult to target with a vaccine? HO: There was initially euphoria when the cause was found, particularly when the NIH announced their papers at a press conference. ZIERLER: This is Gallo's work you're referring to? HO: Yes. The NIH director, Margaret Heckler, was there, and she in fact told the world, "This will lead to a vaccine in a few months." And here we are; 40 years later, we don't have a vaccine. ZIERLER: Did you have misgivings at the time? Did you share that optimism? HO: I didn't know what to think. I was excited about the discovery, and I knew I had a lot of work to do. But a vaccine was probably going to be made by a company, and so that's not something we would necessarily focus on, at that point. Yeah, many people thought that might be a bit optimistic, but hey, a lot of us were a bit optimistic at that time. In the historical records of the AIDS pandemic, her press conference proclamation is going to go down in history, because that has been shown many, many times in the ensuing decades as how wrong we were. [laughs] ZIERLER: Scientists are fallible, too, just like everybody else. Last question for today—when was it time to move on from Mass General, and what were you looking for in your next opportunity? HO: I was at Mass General from 1982 through 1987. During that period, you could say it was highly productive for me. I was walking around picking all the low-hanging fruits in the field. By then, even though I had just started the postdoc, three years into it I was sort of a new hotshot working on retroviruses at Mass General and Harvard. There were very few people working on that. Essentially, UCLA Medical School and Cedars-Sinai Medical Center brought me back to be an assistant professor. They knew that I was trained there, and my family was in L.A., so they made me an offer. By then, Marty Hirsch had been a great mentor to me, and everything I did I owe to him, because it was his lab, his resources, his wisdom that allowed me to do what I did. But by then, I was the retrovirus expert within that institution, and probably at many other institutions, so I felt it was time that I could run my own group and pursue my own research, using my own support. The opportunity in 1987 allowed me to do that. ZIERLER: There's a pattern in your career, going back and forth from Los Angeles to Boston at this point. [laughs] HO: Right! From there, I came to New York, and people expected me to bounce back to California, but now, I've been in New York since 1989. ZIERLER: We'll pick up on in our next talk. Thank you so much. [End of Recording] ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Tuesday, February 15th, 2022. I am delighted to be back with Dr. David Ho. David, it's good to be with you again. HO: Good to see you again. ZIERLER: Today, we're going back to the late 1980s when you come back to Los Angeles. The first question there is, now that you have an opportunity to start your own group, what is the game plan? What are the big topics to tackle? Who are the people to recruit? What are some new ideas in the field that define what you're going to do at this stage in your career? HO: Obviously I was still interested in doing HIV research, and that's what I focused my lab on. It's pretty much a continuation of the interest that I had worked on in Boston, under the category of HIV pathogenesis, trying to understand how HIV damages the body, specifically the immune system. It was at this juncture that I also began to have an interest in antibodies directed to HIV and how they might play a role in controlling the replication of the virus. Those were the principal areas that my lab focused on. I had to hire some technicians and postdocs over the period of the first year and build a small team of half a dozen people to help me carry out the work. ZIERLER: What was the promise in those early years of antibodies? What was it thought they might be able to do? HO: While back in Boston, I had reported that a serum from infected people could neutralize HIV, so there clearly was some antibodies that targeted the virus and inactivated the virus. I wanted to study more, with the idea of trying to induce such antibodies with, in the future, a vaccine. Of course that goal has never been achieved by me or by the field, but I was among the first to report that antibodies could neutralize the virus, and so I wanted to continue that line of research. ZIERLER: Were you involved at all in the 1986 National Academy report on confronting the AIDS crisis? HO: No, I think that was a collection of more senior figures. I was a lowly assistant professor, so I was not part of that. I think figures like David Baltimore were very much involved in that process. ZIERLER: Did it change the field at all in terms of who was interested, funding opportunities, conversations around public health? What impact did this report have on the research? HO: While the White House was not focused on it, at least the scientific community gave it a high priority and assembled such a distinguished group of scientists to map out a plan forward. Folks like myself at a junior level paid attention to what they had to say. It certainly had a great deal of influence and pretty much validated our commitment to this field, that such prominent individuals paid so much attention to it. ZIERLER: A recurring theme in your work, even up to this point—what was the divide in your new group in Los Angeles between access to patients, working in a clinical environment, and simply fundamental research in the laboratory? HO: The last time we spoke, I emphasized the fact that I tried to bridge basic science with clinical practice. At this juncture, I was not only doing lab work; I was attending on the medical service, attending in infectious diseases, and so I was partially involved in patient care and in consultation. My research—the antibody part probably was more basic, but the pathogenesis part, how the virus is affecting patients obviously is in that space bridging the two areas. ZIERLER: At this point, were pharmaceutical companies becoming more and more interested in possible drug therapies? HO: Oh, by this point, by the time I got back to L.A., AZT was in the process of being approved. There were drugs that were also analogs of AZT that were being tried. Aside from, as I mentioned, the former Burroughs Wellcome and now part of GSK, it was clear many other companies were jumping in, like Abbott, like Merck, like Bristol Myers Squibb. Many of the big pharmaceutical companies were involved in trying to come up with drugs. ZIERLER: What impact, if at all, would you say, did the ACT UP protesters have in getting some of these companies interested in therapies? HO: By this point in 1987 or 1988, it was pretty clear to everyone that the infection had spread very extensively throughout the country. Some of the surveillance testing revealed lots of antibody-positive individuals, so it was clear that there was a big market. Of course ACT UP, they played a big role, but I don't think they needed to motivate the pharmaceutical companies. The pharmaceutical companies had already decided that this was a big area they need to get into. Where ACT UP had a role is to make sure that once promising agents are out there, that the regulatory process through the FDA is facilitated. ZIERLER: What role did Anthony Fauci play in all of this, both from the political side in getting the Reagan administration more involved in AIDS research, and having the NIH more involved in bringing drugs to market? HO: Fauci, a few years before this period, had become the director of the NIAID. Of course, this would fall within his institute at NIH. He himself was always interested in topics of this sort—infections, particularly immunity—so he was not only involved as the institute director, but he was involved as an investigator. Of course, despite the lack of attention by the Reagan administration, the NIH did pay a lot of attention. Tony was very, very active in directing the funding priorities. Naturally, in that position, he also became a target for ACT UP, to put pressure on him to appropriate more funding, and to make this a priority. I think initially, there was a lot of pressure and some hostility, but I think Tony, over a few years' time, learned how to make them a partner in the process. ZIERLER: I remember so clearly when Magic Johnson announced that he was HIV-positive, what a major national news story that was. Do you remember where you were and what your initial reactions were when he made this announcement? HO: This would be a few years after the period we're talking about. His announcement was 1991. I guess you don't know this part [laughs]—his status was uncovered through a regular insurance testing, as part of getting a new life insurance policy, and he was found to be positive. That of course was a shock to him and his—initially only to him and his agent. Then his agent, through a physician, contacted me, so I was involved in confirming his diagnosis. His blood was sent to my lab. We confirmed it not only with a regular antibody test, but with a detection of the virus in his blood. This was late 1991. Then, I flew out to L.A. to speak with him and his wife, who was pregnant at the time. Fortunately, her test came back negative, so he did not pass the virus to her, and therefore there was no threat to the fetus at the time. It was after about a week, he was very straightforward in wanting to come out and tell the world, and of course I concurred with that. I think something like this, you cannot hide it for long, and therefore it was better to be proactive. He made that decision, with the concurrence of the physicians guiding him. Of course he also made the decision to retire right there and then, because up to that point in 1991, it was pretty much a death sentence, it was only a matter of time, and therefore he felt that it was best to retire. As you know, he then called a press conference and almost immediately blurted out his status and the fact that he was walking away from basketball. I was involved behind the scenes, and I have been taking care of him ever since. ZIERLER: As you said, in 1991, a HIV+ diagnosis really was akin to a death sentence. Is that to say at that point that there really were no effective treatments for lifelong management of HIV? HO: Yeah, I think the period in the early 1990s was the darkest, in terms of treatment, because there was a lot of promise when AZT first emerged, and then there were drugs like ddI and ddC that came along, and there was a lot of hope. But when the clinical trials were done either individually or in dual combinations, there was hardly any benefit for more than a few months, so that was the most depressing period. By then, so many more people were infected and had progressed to AIDS, and therefore the death toll was great, nationally and internationally. As physicians who are used to treating infections, there was not much we could do effectively here against HIV/AIDS, so it was a very depressing period. On top of his announcement, people realized, hey, this superstar in basketball was probably going to die soon. He himself pretty much had that belief in him. But we tried to tell him that there's more stuff coming along, because we had some visibility into that, not just the drugs that block reverse transcriptase, but there was already a nascent effort to block other enzymes of HIV, namely the protease. By 1991, I was already working with several pharmaceutical companies on protease inhibitors in the laboratory; not at the clinic at that point. So we made it clear to—I call him Earvin—Earvin "Magic" Johnson—I made it clear to him that there was hope, and you just need to hang on, and that was the attitude. We treated him with whatever was available at the time, to buy time. Then, by 1994, some of the protease inhibitors were showing promise, along with the combination of a few other drugs, and so he was put on the combination probably a year before much of the world accepted that concept. ZIERLER: Given the taboo surrounding AIDS in the 1980s and its association as a so-called "gay disease," what do you think the cultural and public health significance was when Magic Johnson made this announcement? HO: I think first of all it brought a lot of attention to this disease. Related to your question, it sort of helped to dispel the notion that this was strictly limited to gay men. Prior to that, the most prominent case probably was Rock Hudson, but it was widely known that he was homosexual. But Magic Johnson's case, he was clearly heterosexual, and had numerous sexual partners, and therefore that this is a sexually transmitted disease; it's not restricted to gay men. In fact, by then, it was quite clear in other regions such as Haiti and Africa that this was largely a heterosexual disease, transmitted by sex of course. His announcement certainly shook the public and put a spotlight on this disease, and brought attention to the fact that anybody could catch this. ZIERLER: What about the perceptions that, as a celebrity, as a sports superstar, Magic Johnson had access to drugs that almost everyone else did not, and that there might have been something unfair about that? What were your thoughts at the time? HO: That's always the case, in medicine. Medicine, to this day, in every aspect there's lots of inequalities. Patients in America have better access than patients in sub-Saharan Africa to good therapies. Even in America, there are different levels of care. That's always the case. Obviously, as physicians, we take care of our patients the best we can, regardless of who they are. And yes, I have had Magic Johnson as a patient. I had regular patients who had early access to therapy, because they happened to fall into my care, and I have knowledge and I have connections that would allow them to take experimental medicines probably a year before others. ZIERLER: Is it fair to say that Magic Johnson is your earliest and most successful patient in the entire HIV saga? HO: He's not the earliest, but he's one of the earliest to get the good combination therapies. Of course his status is well-known to you and to the world, that he has done just fine for over 30 years now. He lives a normal life. He has to take a pill each day, but that's about it. ZIERLER: On the flip side of the unfairness question, what was the value in the world seeing that with the right treatment, even at this early juncture, HIV infection did not need to mean a death sentence? HO: Yes, indeed, that is correct. You know that he's the poster child for what therapy could do for an HIV-infected person. Obviously it's happening to lots of people. In fact, today it's happening to about 25 million people who are being treated with such medicines, and successfully. But few would have the public prominence that he does, and so he is often held up as an example of what good treatment could be. ZIERLER: What were the earliest discussions that ultimately led to the creation of the Aaron Diamond AIDS Research Center? HO: I'm the founding director, so I'm part of its creation. But even before me, there was Mrs. Irene Diamond, who is a very special person, dear not only to me but many in the New York community. She was married to Mr. Aaron Diamond, who was a Harvard Business School grad and became a very successful builder and real estate developer in New York City and made a rather sizable fortune. She, on her own, had been out in Hollywood, in the early years, from I would say the 1930s, 1940s, 1950s on. Before marriage, her name was Irene Lee, in Hollywood. She actually discovered the script for Casablanca, and today she would be called the producer. She was a female working for Samuel Goldwyn and all these big names in Hollywood. She was a very successful person in Hollywood. She produced—today we would say—she produced Casablanca, got the Epstein brothers to write the screenplay, and brought it to the screen, to the big screen. She discovered stars such as Bette Davis, Burt Lancaster, Robert Redford. She was on the board at Sundance. I'm giving you her background that's totally unrelated to AIDS. Of course she returned to New York after marriage and was a major supporter of arts in the New York world, a major supporter of the ballet, of Lincoln Center, of the theatres. By the early 1980s, as the AIDS epidemic was developing, they had created a foundation to give back to New York City. The paradigm for running their foundation was rather unique. They essentially set aside$200 million to give it all away. Not giving the interest of the corpus of the endowment, but rather giving away the corpus over a ten-year period. They chose certain things to fund, including the arts of course—Lincoln Center, Julliard. Jazz at Lincoln Center was created in part due to their funding. Also they gave money to Human Rights Watch. So they had a number of arts and liberal causes that they supported.

They also witnessed the devastation of HIV/AIDS in New York City. Of course Irene socialized in a circle that involved many artists, many of whom were affected by this condition, so it touched her. As she looked around New York City—and this is a story she told—there was little going on in New York City, despite it being the epicenter of HIV/AIDS in the U.S. She felt badly about that, and in the late 1980s approached the health commissioner. This initially was under Ed Koch as the mayor. Then the commissioner was asked what she could do, and the commissioner said, "Well, if you're interested in research and finding a long-term solution to this problem, we could create an institute. The city would join forces with you. We'll provide you the laboratory space you need." So she and her foundation went to work. This was during the transition from Mayor Koch to Mayor Dinkins. It was finalized under Mayor Dinkins' administration. But then the foundation provided financial support, the city provided space. Initially NYU provided the academic linkage. Of course, that academic affiliation switched to Rockefeller later.

She created a board, and the board went looking for recruits. I was still back in L.A. when I was approached in 1989. This was only approximately two years after I had returned to L.A.; I was approached by this new entity for an interview, as a young assistant professor. I did not know that they were interviewing me for the directorship, which in fact was the case, but I thought I was being interviewed as one of the scientists. But I hit it off with Irene. She asked for my vision. I laid out a plan. In that process, I realized that despite my junior status, she was keen in having me. I was 37 at the time.

ZIERLER: What was your plan? What did you say to her that resonated?

HO: I said if I were the director, I would continue to focus on HIV pathogenesis and try to bridge the basic science with the clinical components, because that was my strength. I would build in that specific area by recruiting other scientists that would complement my skill set. I would go and recruit immunologists who are focused on the immune system and how the antibodies or T cells would attack the virus and help control it. I would recruit molecular biologists who would, again, complement my skills, and we would work as a team. I think they must have liked that vision. I have to say, they did interview a number of very senior folks from the NIH and from Harvard, but in the end, perhaps against advice of some academics, Irene Diamond made the decision to go with a young scientist. I have accomplishments under my belt, so I think she was sufficiently confident. But I think if it weren't for Irene Diamond, the directorship would not have been offered to me, in the sense that Irene Diamond, her career in Hollywood was to discover young stars rather than betting on familiar faces.

I think the academics in the selection committee probably would have preferred going with somebody who's more senior and more secure and less risk. She gave me the offer. She's like a mother to me, for many years. By then, she was already 78 or something like that, approaching 80. We had the best relationship, I think, outside of my own mother. Each month, she would invite me to either her apartment in the city or her country home and we would have dinner, and we would then talk, and before we know it, it's 3:00 a.m. She wants to know everything about science, about what we're doing. Even though she probably did not fully grasp every aspect, but she got into it, and that's the kind of person she was. With her support and with the recruits that I brought in, I think the Institute went from scratch to probably prominence over a five-year period. I recruited only people who came out of postdocs, so we were all junior. It was an institute of junior faculty members, and we became very, very successful over the initial five, six years.

ZIERLER: Did you take that initial group that you had just begun building up in Los Angeles to the Diamond AIDS Research Center? Did they all come with you?

HO: I think two thirds of them came with me. Some have family reasons for not leaving L.A. But they came as postdocs and technicians, not as the additional faculty members. In fact, several of them are still with me, 30-some years later. [laughs]

ZIERLER: Was it conceived to be a totally independent institution? You mentioned NYU at the beginning.

HO: It would run autonomously, and fiscally, it would be independent. But of course an institute of this sort would need academic affiliation. All the scientists would want some academic titles. This would be akin to the Broad or the Whitehead, except Broad came much later. Whitehead was some years before. They are situated pretty much on campus. We were situated next to the campus of NYU Medical Center, but we functioned as an independent unit, although our academic titles were within the medical school.

ZIERLER: Did the academic affiliation give you courtesy appointments? You could sit on committees, you could teach if you wanted to, those kinds of things?

HO: Yes. By then, I was a tenured professor at NYU School of Medicine, and I had all the rights and privileges, and responsibilities.

ZIERLER: It's such an opportunity. What did you want to build for the research center? What was most important to you?

HO: We didn't know which aspect we would make our impact on this—pandemic, by then. Our fundamental mission was to do science and contribute to controlling this pandemic in any way we can. It was not specified how. It was up to the scientists who were brought in to make the contributions. It turns out that our contributions came from understanding pathogenesis leading to new treatment paradigms, and then launching the clinical trials. We were perfectly situated, because we were in that space between basic science and clinical science, and we were bridging it, and we took the basic understanding and just, without a hitch, transitioned right into the clinical part. That's my strengths, and that was the strength of the colleagues that I had recruited.

ZIERLER: To go back to something you said in an earlier discussion that was so important, the quantitative approach to biology that you learned at Caltech, in what way in the early years of the Aaron Diamond AIDS Research Center was taking a mathematical or even a computational approach to replication rates, mutations of the virus—in what way was that approach so fundamental for the advances that were made in the mid 1990s?

HO: I think it was the most crucial component. I think we discussed the fact that once we administered the protease inhibitors, we see the viral load drop precipitously. As virologists, as physicians, you just celebrate that success. You're controlling the virus. But there's a deeper question buried within those results, and that is, "Shouldn't we understand why the virus is dropping so quickly, and what is it telling us?" By this point, it's 1994. I think last time we talked about the papers from 1989. The underlying interest was already there, and then by 1992, we're already saying, "It's the virus, stupid." Seeing those results, it immediately clicked that prior to our treatment, the dynamics of the virus must be so rapid because with the administration of the drugs, we were shutting off virus production, so the viral decline is so dramatic because prior to the intervention, both were equally high. This is something that a high school student could figure out if you really focus the question exactly right for the high school student. Then the high school student with maybe AP calculus could probably write the differential equations. By this point, I'm many, many years away from differential equations, but I know conceptually, so I understood what was going on and realized that actually more than the success of the drugs, we are uncovering, unraveling a fundamental discovery, and that is the dynamic nature of the virus.

It's pretty much the fact that having that Caltech background, the quantitative part comes almost automatically, whereas that is rather foreign to most virologists, to most physicians, and so they don't ask the next question. That's what we did. It sounds so simple after—when I first gave this talk to a national and international audience of 5,000 or 6,000 people, everybody said, "It's so obvious." Because when you explain it properly, it's so obvious, but nobody bothered to ask the question. Those results were pretty well accepted almost immediately.

ZIERLER: The famous phrase "Hitting HIV early and hard" of course comes from your landmark paper in 1995. What was both the science and the public health implications of this approach? What did you mean by hitting HIV early and hard?

HO: By then, we didn't have a complete picture, but we had a pretty somewhat blurry picture of what's going on, but that was sufficient to tell us that the virus was highly dynamic. It was replicating at high levels, and associated with that is a high destruction rate of our immune cells. If the virus is doing that much damage on a daily basis, then we must hit it as early as possible, right? It's doing a lot of damage every day. Why wait a year? Why wait two years for the virus to take even greater toll? The early part.

The hard part comes from the math, again, because once we know the replication rate, we also could calculate the mutation rate, which is known, for reverse transcriptase. It has been known for some years before HIV, that the error rate was so much higher. If you have a huge number of replications each day with a high error rate, you're going to create many mutants. Then the genome is only 10,000 bases long, and so you could calculate, what is the probability of mutation at each position? Basically, the math told us that the virus could mutate at every position to every other substitution, every single day. That means the virus is capable of evading our drugs, very easily, in a matter of a day or two. However, if you say, "Well, I want to use now three drugs, and I want to force the virus to have this mutation at position one, another mutation at position two, and another substitution at position three simultaneously"—the probability of that occurring is a small number here, multiplied by another small number, multiplied by a third small number. That, we could calculate, how probable that is, and it becomes exceedingly improbable. That's why in 1995, we jumped to launch three clinical trials using triple drug combinations, and every single of them resulted in durable control of the virus. It's so obvious from the math. A year later—and we can't just watch the virus for a few weeks or a few months; we have to show that there's a prolonged period wherein we could control the virus, so we waited for a full year to show that we could durably suppress the virus with the triple combination, and that's the beginning of combination antiretroviral therapy. Immediately, the "hit hard" part was accepted, because we showed it. But the "hit early" part remained controversial for a long time. Now, it's part of our treatment principle, but "hit early" was controversial for a good ten years.

ZIERLER: Exactly why was it controversial?

HO: People say, "Show me the data that ‘hit early' would be beneficial." My argument was, "Well, you know what the virus is doing, and it's depleting your critical immune system, which we know we cannot replenish. You're running low with your gas tank, as you let the virus go, and you cannot replenish; you can only stop the draining of your reserve with therapy, but you seldom could replenish." That was one argument. People would say, "Show me the data that treating early would be useful." But then for every other infectious disease, we always treat as early as when the diagnosis is made. But in this one, people said, "Show me the evidence." It took ten years to do the trials for comparing early to late therapy. Surprise, surprise; early is much better than late. Now, the position we put out in 1995 is the standard. Today, you diagnose HIV, you immediately treat, and you treat hard, with a combination of drugs. But this is how science is done. To me, it's a little silly, because if you visualize what the virus is doing, why would you wait? You could argue that early on, some of the drugs have more side effects, and that was the concern. It's probably colored a great deal by the side effect of the medications.

ZIERLER: Given the urgency, as you explain it, of hitting early, what did that mean in terms of testing regimes, the importance of achieving an early diagnosis through rapid and accurate testing?

HO: You can't treat people you don't find, right? But by then, most of the high-risk communities were getting tested quite a bit. Certainly among gay men, there's no question. There's lots of voluntary testing. But also we knew that this virus was penetrating into other communities, and into heterosexual communities, into urban communities of color. In some of those communities, the testing was not routinely done. Then what you have is patients showing up late with manifestations of AIDS, and some still dying, when one could arrest the progression of disease with drugs.

ZIERLER: A somewhat tangential question—at this point in the mid 1990s, four or five years after the death of Ryan White, were blood supplies sufficiently safe from HIV infection? Were hemophiliacs at risk at this point?

HO: No, not by that point.

ZIERLER: We talked about the discovery of the virus in 1983, 1984. By 1985, blood tests were available, and blood supply was largely well guarded, except for a few units that slipped through because people had virus but had no antibodies. That's in the early, early phase of infection. So some got through, and then we learned to protect against that as well, by testing for both antibody and viral proteins. The blood supply by the mid 1990s was well guarded.

ZIERLER: To go back to the pharmaceutical companies, what role did they play in the combination approach to antiretroviral drugs, which by this point were showing that you could get the HIV down to levels that were essentially undetectable?

ZIERLER: The drug companies were active. They were active in developing many of the reverse transcriptase inhibitors, and the protease inhibitors up to this point. Those were the two major classes of drugs. Of course, later, we had other classes that came. They were very active. They knew that there was a huge market, and that market probably needed to be treated chronically. It's not like penicillin you take for a course of a few days; this could be a course of many years or a lifetime. And this was a lethal disease. So the companies were committed. All the major ones were engaged. Except each was developing their drug, and some may have a couple that they were developing.

No one at that time was developing a cocktail. Once we recognized this, as I said earlier, we launched three trials. They were quite similar, actually. One was using a protease inhibitor from Abbott, one was using a protease inhibitor from Merck, and the third was using a protease inhibitor from a small company called Agouron. Then we combined the protease inhibitor with two drugs developed then by Burroughs Wellcome, AZT and 3TC. AZT and 3TC was used in all three trials, but each paired with a different protease inhibitor. They showed pretty much the same results. We were in a position to do it because we had the hunch that it would work, from the math, from the dynamics. We were a small unit, we were nimble, and so we could talk to each of the companies very quickly. Of course they were eager, because they already knew our results, and what we were espousing, and they wanted to be there with us to see if this would lead to something very positive. And we're not part of the larger NIH network that would take months to work out a protocol, to get committees to agree. You do science by committee, you're going to be very, very slow.

ZIERLER: Was the FDA an ally in this? Did they help move things along?

HO: They had to approve these trials. Of course by then, in the mid 1990s, they had all the pressure from the activists, so the FDA let us proceed with the trial within weeks of submission, so there was no issue. The pharmaceutical companies not only gave us the drugs; they funded the studies, but everything else was ours. We did all the clinical part. We did all the laboratory measurements. We drew the conclusions. And they each shared in the credit as well.

ZIERLER: What stands out in your memory from the International AIDS Conference in Vancouver in 1996 where there was so much excitement surrounding these findings?

HO: That was in the Summer of 1996, but by then, our results were leaking out. We haven't waited the full year, but people knew. We had patients who were bedridden, and they got up and went back to work.

ZIERLER: These are like miracle stories, essentially.

HO: Right. Lazarus syndromes, right? It was pretty clear that we were witnessing something fundamentally different from previous therapies, and so results were leaking out. Then The Wall Street Journal, prior to the meeting, had a full-page article essentially getting an early indication of what we were seeing. Actually the person who wrote that story, Mike Waldholz, went on to win a Pulitzer for that piece. So there was a great deal of—but no one had heard the official presentation, so I was invited to—the organizers knew that we had data that was very promising, and the organizers asked me to give a plenary talk. I had never had a scientific presentation with more media attention focused on me. I would say there were hundreds of TV cameras in the back of the room filming the whole lecture. Then of course there was some sort of press conference to follow.

ZIERLER: You mentioned earlier some of the naysayers about the go-early approach. Were they a factor at this point, or they were drowned out, essentially?

HO: They were not a factor, because by then I wasn't repeating that line of hitting early and hard, just "Here are our results for a year, in three clinical trials." Focusing actually largely on one, to show, in detail, because there wasn't time to cover all three, but they basically showed the same thing. Those results are not disputable. The patients got up and became well again and functional. Viral load measurements by then were routine; everybody could do them, and they'd surely know we know how to do them, so no one disputed the results. I could say that aside from the media attention and the scientific attention, I think the most prominent was from the affected community. I think many of them were in tears, that there was something this promising that's on the horizon.

ZIERLER: Last topic we'll touch on for today—of course in 1996, you are named TIME magazine's "Man of the Year." First, when did that news break? Where were you when you heard that you had been chosen for this honor?

HO: That was a gradual process. Early in that year, TIME magazine did a piece on some of our findings, and of course they were there to cover the Vancouver international AIDS meeting. I had developed, by then, a relationship with some of the reporters from TIME magazine. They approached me late in the year—this was several months before December—late in the year, to say, "We'd like to do a follow-up story." Of course I agreed, and they interviewed me rather extensively about all the work that we have done in the preceding year. It was very science-focused. Then I told them that within a short time, I had to go back to Taiwan, where I was born and raised. They said, "Well, can we come with you?" And they did. That was a little curious. They said, "Well, we want to do a bit more personal aspect of your story." So they spent a couple days with me, one in the capital city, and one in my hometown.

ZIERLER: What were you doing there? You were just visiting family?

HO: Yeah. Obviously I went for business reasons, to give talks. By then, people already knew of the Vancouver international AIDS meeting, so I was getting a lot of requests. Of course, coming from Taiwanese physicians and scientists, I couldn't say no. They were obviously proud of the work we had done. I went back for that reason, and they came along. That raised a lot of suspicion. I may have the dates a little fuzzy, but toward the end of November, they sent a photographer over, and the photographer asked for a whole day. Normally, you give them 30 minutes, they take a few hundred pictures in those 30 minutes, and then you'd be done. They said, "We need a whole day." There was a very astute person who worked with me to say, "Hey, do you know this guy Greg Heisler? He only takes covers."

ZIERLER: [laughs]

HO: I said to the reporter, Alice Park—she and I still talk to each other from time to time—"What's going on? Why are you going to Taiwan and why are you doing this?" Then she reluctantly said, "Well, we're not supposed to say this, but this could be the end of the year story." I said, "What does that mean?" At that time, they called it "Man of the Year," not "Person of the Year." They revealed that was a possibility. But she also said, "We usually do four or five of these, and then it's up to the editorial board to make the final selection." Naturally, I asked, "Well, who are the other ones?" [laughs] She told me, well, it was Bill Clinton, Bill Gates, and Mother Teresa. I said to my colleague who informed me about the photographer, "Let's forget it."

ZIERLER: [laughs]

HO: I really did not think seriously about that as a possibility, because if you look back, it's usually a public figure who receives that. I didn't pay much attention and basically found out a few days before the actual publication. Then I knew there would be lots of focus, so my family and I just left New York and went to ski in Vermont, so I was not available to the media for follow-up, because I thought that was already too much attention for a scientist and wanted to avoid even more media attention, so I left town. The funny part was—I was curious enough, in Vermont, to walk into a drug store, to buy that issue of TIME magazine. [laughs] Of course, I don't know if you've seen the picture, but there's no way—with the reflection of sunglasses, with colorful dots all over the place—so I bought it, and I put it down on the counter, and the guy says—I forget the price—"A buck, seventy-five," or something like that. [laughs]

ZIERLER: It's such a unique honor, besides, later on, Albert Einstein being named Person of the Century, and in 1960 a group of U.S. scientists. After those initial days of media frenzy, what were both the long-term opportunities and challenges of being accorded this kind of attention? Let's start first with the challenges. What did that mean for the Aaron Diamond Center, for example?

HO: By then, to our colleagues, to our peers, we were very well known. The accomplishments that we had in the preceding years were rather noticeable to the research community. But with this honor, it brought a different type of recognition, from the public, from many community organizations, from the media. It certainly elevated our prominence and my own reputation, but that came with a lot of responsibilities. There was a huge burden on the shoulders that came with that TIME magazine honor. I took it that way. In some ways now I have to be one of the spokesperson for the field. By this point, I'm in my early forties, so still a pretty young person, working in the field. Most of the people with whom I communicated are older than I was. But I also recognized that TIME magazine honored me as an example of the progress made in the whole field. They know I didn't do everything myself. We did the trial, but the drugs didn't come from us. The drugs came from the pharmaceutical companies. They could have honored a group of scientists. That may have been a better solution. In fact, they wrote about it in that same piece, that they wanted to pick one person to exemplify what has been achieved. We did the fundamental work to reveal the dynamics, which then led to the treatment strategy, which then led to the actual clinical trial.

ZIERLER: Last question for today, the attention that you received as a result from this honor, did that allow you or encourage you to pursue new areas of research that you might not otherwise have? For example, in the late 1990s, when you started thinking about the origins of the virus.

HO: Yeah. Obviously by then, our reputation was stronger. Our funding was larger. We were able to do more. The Institute that I had helped to form had a large critical mass, so we could pursue many different things. We began to think seriously about cure, about vaccines, both of which have not been achieved yet. We thought about where these viruses came from. That was always on our mind. We were able to diversify quite a bit and tackle some of the biggest challenges that remained in the field. So it really propelled us tremendously.

ZIERLER: On that note, we'll pick up next time when we get into the turn of the century, and we'll bring the story right back up to the present.

[End of Recording]

ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It is Tuesday, March 8th, 2022. Once again, it is my great pleasure to be back with Dr. David Ho. As always, it's great to be with you.

HO: Great to come back.

ZIERLER: David, a very current question to start things off. Obviously right now the unfolding horror in Ukraine is on everyone's mind. From your perspective, from your vantage point, when you look at either the war in Ukraine or civil wars in Africa, from a public health perspective with the focus that's most important to you, in virology and immunology, beyond the acute problems that we see in public health with all wars, what are the kinds of things you're looking for, whether it's a war in the middle of a pandemic right now, or an ongoing HIV crisis in Africa? What are the things that you're looking at, in moments like this?

HO: It's obviously horrifying to see the devastation caused upon the citizens of Ukraine. Obviously I see what's happening with the refugee situation, and I see crowding in various refugee centers. It's got to be bad for the spread of SARS-CoV-2. Fortunately, it's happening at a time when the prevalence of the virus is on the low side, but you could imagine that if there's a case in there, you could have superspreading events. Aside from the other consequences of war, I see it from the perspective of the pandemic, and it's got to be bad. Then there's probably a total lack of healthcare infrastructure in such places, so if one should get really sick, there's probably not much one could do. In terms of civil wars and other conflicts in Africa and HIV, we know for decades that it's always bad. Displacement of people, interruption of normal life, it's bad. People move around, develop new relationships, and lack of preventive measures are all going to lead to more spread of the pathogen.

ZIERLER: Another topical question—the last day that we spoke, I saw a news alert that a woman was cured of HIV. First, what are the biological thresholds to achieve a cure, and what does this mean in terms of the ultimate goal of eradicating HIV from the human population?

HO: Let's talk about that one case. It's not the first case. The first case happened many years ago, known as the Berlin patient. He's actually an American named Timothy Brown, who was cured of HIV. These cures happen through extraordinarily means. They typically have developed another condition—leukemia or lymphoma—that require chemotherapy and radiation therapy followed by a bone marrow transplant. When you do that, you wipe out all the existing cells, essentially. By doing so, you also wipe out the cells that carry the virus in a latent fashion. Then, when you do the bone marrow transplant, you select donors who have a certain genetic defect. In this case, the defect turns out to be protective, so their cells are not susceptible to HIV infection. This has been achieved in a few individuals, but you wouldn't do this to a person who doesn't have leukemia or lymphoma, because the intervention is worse than taking a pill once a day. These people are not going to have a normal lifespan because of what they have gone through. This new case is important because it shows us that cures could be achieved, but at this point only through extraordinarily means.

ZIERLER: So a cure does not mean one should expect to live a long and healthy life; It just means cured in the narrow definition of eradicating HIV from this particular person?

HO: Right. But what you went through with chemotherapy, radiation therapy, and bone marrow transplant means that your body has taken quite a toll, much more than taking the antiretroviral therapy once a day.

ZIERLER: All of which is to say, then, that this course of treatment would never be part of the public health arsenal going forward in otherwise healthy individuals.

HO: No, no. It's just conceptually important, but it's not practical.

ZIERLER: Picking up on our conversation from last time, going back to the late 1990s, you mentioned briefly your investigations into the origins of HIV. What aspects of this research was simply detective work that fascinated you, and where was there perhaps a motivation because knowing the origins of HIV might have clinical value?

HO: It's pretty clear that the origin had to be Africa, because related viruses are only found in African primates, including chimpanzees, gorillas, and other primate species. You don't find them in the Americas or Asia or elsewhere. Then of course we knew sometime after the early 1980s there was a lot of cases in sub-Saharan Africa that were being reported. That's consistent with an African origin. Then I recall reading a paper in The Lancet from years ago, from near the beginning of the HIV pandemic, that somebody had detected an HIV-positive sample in an old blood collection that had been taken for a whole different purpose. This was reported by CDC. That was a case from 1959, so the virus was already around in 1959. Aside from the report that there is antibody against HIV in that sample, I wanted to see if there are any HIV sequences. This sample essentially had dried up. It was a blood—serum sample. It had dried up. But we know viruses are in serum or plasma. We amplified that viral sequence in pieces. We did not get the whole genome; we just got small pieces. But by amplifying those small pieces out and sequencing them, we determined that it was indeed HIV, so we confirmed that 1959, HIV was in a person in Kinshasa, in the Democratic Republic of Congo. At that time, it was called Zaire.

We confirmed that, and then we did what's called a phylogenetic analysis, comparing that sequence to all the other available HIV sequences. By the time we did this, it was already clear that HIV sequences represent a starburst, if you were to draw it, as if there was a Big Bang and then you have these sequences radiating from the center. Interestingly, this sequence was fairly close to the center. By using the molecular clock based on the evolution rate, we were able to say that if HIV had evolved this much over 20 or 25 years, then this was the sequence in 1959, when was the Big Bang? That, we projected—it was not very precise—somewhere between 80 and 120 years ago. So it was roughly a century ago that it probably jumped the species from most likely chimpanzee, because they carried the closest virus, and then spread in very indolent, insidious, quiescent ways in the human population without much notice. If you think about it, in those days, people didn't travel very much. Transport was not quite the same. Population density wasn't quite the same, The virus could not spread as quickly. Probably sexual practices were different. We still think today that the origin has to be somewhere in that region of Africa. That's what we did, and really helped shed light on how this thing may have evolved over 100 years.

ZIERLER: Looking back at the H5N1 bird flu, what did this tell you about the possibility of pandemics of zoonotic origins?

HO: That was very scary. H5N1 was spreading very, very rapidly among avian species and doing a great deal of damage. There was reported infection spread to humans, and then some of the humans infected by this novel variant were coming down with severe influenza infection, and in some cases death. Fortunately for us, there was not a lot of human-to-human spread, but the pandemic potential was there. We know that the virus only needs to make a few mutations to confer the ability to spread from person to person. That generated a lot of concern, that there was so much of that virus in the bird population, and if it got into humans with a few key mutations, there would be a pandemic. That never materialized, but it certainly put a scare in all of us.

ZIERLER: Have there been public health measures put in place that lessen the likelihood of a bird flu pandemic cropping up in the future?

HO: Yeah, I think that certainly pushed the surveillance program for influenza forward. There was very close monitoring of influenza viruses in human and avian and other animal species all throughout the world. In fact, the current COVID surveillance program was added to the influenza surveillance program, so that formed the foundation for what we do with COVID today. A lot of measures were taken to address H5N1 by wiping out a lot of bird populations, particularly the farm chicken population. They had to cull a lot of those animals to keep the spread down.

ZIERLER: Today, do we see better practices in industrial farming as it relates to raising poultry?

HO: I'm not sure I know the answer to that, [laughs] since I don't follow that, but I'm sure that it's a concern to them. Once you have a virus go in, you probably have to slaughter all the available chickens in that facility, so it would come at a huge economic cost, so I'm sure there's some work along that line, but I don't follow that.

ZIERLER: Moving into the 21st century, the SARS outbreak in 2002, what was your involvement in that?

HO: At that point, I was already helping China with a number of things related to HIV/AIDS, and so I had developed a good relationship with the Ministry of Health and Ministry of Science and Technology. By then, I had been recognized by a number of entities for my work on HIV so I developed good standing with the Chinese officials as a notable virologist. When SARS broke out, China did not have the capability it has today. Its basic research was rather backwards compared to what we are today. They needed a lot of advice, a lot of technological help. I was an official advisor to the Ministry of Health and the Ministry of Science and Technology. From late 2002 through the Summer of 2003, I was there probably six or seven times, each time staying for a couple weeks, advising the Beijing government as well as the Hong Kong government. Then I would stop over in Taiwan to advise the Taiwan government on best practices and also on some of the virologic techniques that they could employ to address the technical aspects.

ZIERLER: Was the SARS outbreak in your memory—did you consider this the first sustained worldwide effort to understand how coronaviruses specifically can cause epidemics?

HO: Yes. It was a surprise, because coronaviruses had only caused the common cold, and SARS had a 10% fatality rate, which scared the population considerably. It's manyfold higher than COVID. Certainly the economic impact on greater China was huge. Hong Kong locked down—well, not locked down the same way, but everybody was scared. Everybody was wearing masks. Everybody stayed home. Property values dropped dramatically. There was a huge economic toll. Compared to COVID, it's nothing—8,000 cases, 800 deaths. It's nothing in retrospect compared to COVID. But at the time, it was devastating. Then over I would say eight, nine months, it was brought under control, and largely because it was not as efficient in transmission as COVID. Also, people did not have higher amounts of virus until they're sick, unlike COVID. COVID, you could carry a fair amount of virus asymptomatically, and therefore you could pass it on to others. With SARS, you were pretty much bedridden by the time you could transmit, so that led to an easier containment strategy. But greater China learned a great deal from that. That's why they responded better at the outset. Even though China could still have done a better job in containing the initial outbreak in Wuhan, but you could see, even locking down Wuhan and then all the other provinces kept the caseload under 1,000 for a year. That's really remarkable.

ZIERLER: For the public health officials, the immunologists, the virologists who were focused on SARS, what were some of the big takeaways about what coronavirus was capable of doing, if previously it was only associated with the common cold?

HO: It told us that it actually could be quite pathogenic. In certain high-risk individuals—the elderly, the ones with underlying conditions—it could be rather severe. That really put coronavirus on the map. A lot of people worked on it for a few years, but once the outbreak was over, people kind of let go of that particular focus, until MERS, which came about ten years ago. MERS only caused a small number of infections, even though its mortality rate was around 30%, so even higher, more deadly, but it didn't transmit very much and never really got out of the Middle East except for a few cases. But that already taught all of us in virology that coronaviruses could be devastating and probably should be elevated to a level similar to influenza as a threat. All that came true with the arrival of COVID.

ZIERLER: As you know of course, during the presidency of George W. Bush, President Bush received a lot of well-deserved praise for his focus on globalizing the fight against AIDS. Were you involved at all with the Bush administration on a policy level?

HO: I was not directly involved. Obviously, I was part of the scientific community that pushed for certain things to be done, including, most importantly in my view, the access to good therapy for sub-Saharan Africans. George W. Bush, as you said, deserves credit for what's called PEPFAR, President's Emergency Program For AIDS Relief. But that came after many other efforts, including from the Gates Foundation, from WHO, from the Clinton Foundation, to lower prices, and for the pharmaceutical industry to agree to make drugs available at cost. Then of course the huge infusion of money from PEPFAR. As scientists leading the field, a number of us weighed in and said, "This ought to be done. The inequity is not right." It's the same discussion we're now having for COVID vaccines, for example.

ZIERLER: Of course I'm sure it would only be speculation on your part, but given George W. Bush's commitment to fighting AIDS, did you ever wonder if this amounted to a historical correction from the relative inaction by both the Reagan and his father's administration when it came to AIDS?

HO: It was really gratifying to see. I didn't agree with George W. Bush very much on many of his decisions and actions, but on this one, he certainly pleasantly surprised many of us by delivering, and actually not just committing the funding, but coming out and pushing and being an outspoken person on behalf of this global effort. This to me is one of the shining spots in his legacy.

ZIERLER: If you could imagine a historian writing about AIDS 50 years from now, what impact historically thinking do you think the Bush administration's efforts will have on this program, this effort, this global effort to rid the world of AIDS?

HO: I think now looking back, there's some 20-plus-million Africans on antiretroviral therapy. These folks would die without that. I think without the PEPFAR effort, yes, some will have been treated, but the number would be much smaller. I wouldn't know how many more are treated because of that, but I suspect that number would be rather large. So it's certainly a remarkable development. Now, that said, there's still millions of people who need therapy and who are not, and so there's a lot more work to be done.

ZIERLER: What explains, then, looking at it from the opposite perspective, the shortcomings of PEPFAR? What will it take so that the 20 million or so that you've cited would cover everybody threatened by HIV?

HO: Some of the cases are not diagnosed, and therefore they're not treated, so there needs to be more extensive testing to identify those who would need the therapies, and not wait until they come down with severe complications. Some of it is related to a necessary testing program that's more extensive. Some of it is just logistics, delivery, and economics. Again, some African countries do it better than others, and it all depends on their basic infrastructure.

ZIERLER: Of course during COVID we have heard so much about monoclonal antibody treatments. Was this research related at all to HIV therapies?

HO: Yeah. The HIV vaccines have been really tough to develop, as we discussed. Decades of work; no vaccine available. People look to the use of drugs for prevention, and that's very successful. In more recent years, people looked to develop monoclonal antibodies for prevention. Much of the effort that was committed to developing HIV-specific monoclonal antibodies resulted in a great deal of novel technologies that were then immediately applied to COVID-19. The rapid development of COVID-19 antibodies came out of I would say decades of work on HIV monoclonal antibodies to come up with the new approaches. My lab was no different. We had developed a lot of skills working on HIV monoclonals, which we then applied and developed the monoclonals for COVID-19 in the course of two to three months, to isolate them, to characterize them, and pick out the good ones. Even though there is only one monoclonal antibody that's licensed for HIV therapy, there are many that are still in clinical investigation, and yet there are now half a dozen COVID-19 monoclonals that have been authorized for use.

ZIERLER: This is to say that the monoclonal treatments that you developed for HIV essentially supercharged the relevance of this for COVID therapies.

HO: Exactly. To a large extent, that is also true for antiviral drugs. Several of the COVID-19 small-molecule drugs really benefited a great deal from our experience in coming up with HIV and AIDS, Hepatitis C drugs.

ZIERLER: You mentioned, of course, the Middle East Respiratory Syndrome or MERS. Comparing that with SARS, what does that tell us about sources of outbreaks and the way that they're contained where they originate? The cultural and sociopolitical aspects of containing an outbreak before it gets out of hand.

HO: From SARS and MERS and now COVID-19, we know that all three of these more deadly coronaviruses came from animals. For MERS, it probably went through an intermediary host, and that's the camel. For SARS, it went through, we believe, the civet cat, which is a raccoon-like animal. For COVID-19, we're not sure. But all three of these coronaviruses are commonly found—let me rephrase that—viruses related to all three of these viruses are commonly found in bats. We believe that's the original source animal, that then spread either directly or indirectly into the human population. Now we know that there are many such coronaviruses. Most of them related to SARS and COVID-19 are called sobical [?] viruses, and we are quite concerned about another sobical [?] virus coming from bats into the human population, causing future pandemics.

ZIERLER: In researching Simian Immunodeficiency Virus or SIV, what aspects of monkey retrovirus have you pursued as fundamental research, and where has the motivation been perhaps translational?

HO: That's not a major area of focus for my group, but we have done some. Others have done more, I would say. For example, Beatrice Hahn at U. Penn has done a lot to understand the related viruses in chimpanzees and related viruses in other non-human primates, particularly monkey species. We now know that the chimpanzee virus that eventually got passed to humans as HIV is actually a recombinant virus that combines several different SIVs from different monkey species. They recombined, jumped into chimps probably long, long ago, and then the chimps evolved this virus, which then passed to humans. All that is really very important to understand how these viruses came about, and how future threats might emerge.

For the purpose of doing experiments, you cannot infect monkeys with HIV, but you could infect them with SIV. SIV is different from HIV, so to do vaccine studies or drug studies or monoclonal antibody studies, we could actually make hybrid viruses that have bits and pieces of HIV with the rest being SIV, and then now you could infect monkeys with the hybrid virus. Such a hybrid virus would allow us to study vaccines and monoclonal antibodies, for example, in a small monkey as opposed to trying to do experiments with chimpanzees, which we don't do anymore. So SIV has been utilized as a tool for us to study HIV vaccine and monoclonal antibodies.

ZIERLER: Tell me about your partnership with the Bill and Melinda Gates Foundation. How did that come together?

HO: I think the Foundation decided on their focus on global health, and of course they wanted to address the health concerns of developing countries. Infections surfaced to the top, and TB, malaria, and HIV were among the top priorities. Of course in HIV the holy grail was still the development of a vaccine. That's naturally what the Gates Foundation focused on. For the last 15, 16, 17 years, we've been funded by the Gates Foundation to do work related to vaccines and monoclonal antibodies. It has been a great partnership. They extended that funding to cover our COVID work recently. We have been continuously funded by them ever since they directed their attention to HIV. Until this pandemic, we had been going there for the annual meeting at the Foundation. They assemble a group of top scientists with the same mission, and that really contributed a lot to science, which we now see as benefiting the research on COVID-19.

ZIERLER: Did you ever have the chance to interact directly with Bill Gates about your research?

HO: Sure, a few times. Not extensive. He does read every proposal that's over a certain amount, and our grants have always been over that amount. He would ask questions, and he would show up at some of the annual meetings, not all of them, and give a speech and take Q&A, so we know he is quite committed.

ZIERLER: What has the Foundation made possible, as a result of your partnership?

HO: I think their biggest contribution is in the translational aspect. They're not NIH. They're not National Science Foundation. They don't want to just fund basic research. They think that's the job of the federal government. They wanted to fund promising strategies that could result in a product that would benefit the developing world. They set their sights on that. For us, working in science, if you have a more product development project, it's very difficult to get funding from NIH, because that's not NIH's mission. If it's basic science, then fine, but if you want to develop a product, NIH doesn't fund that typically. Gates Foundation filled the gap for those of us in academia who wanted to help develop products. Otherwise, the model has always been NIH funds basic science and industry takes over. But industry doesn't necessarily see a great deal of profit when your focus is on the developing world. That's a market that doesn't pay very well. Gates Foundation filled that void nicely.

ZIERLER: It sounds then like philanthropy really fills a vital void in the process of achieving translational breakthroughs that might not be attractive from an economic perspective from industry.

HO: That's absolutely right. You could say Gates Foundation, the Wellcome Trust are two great examples of filling that gap, allowing people in academia to continue their basic research into translational aspects, and still receive funding. Of course, at some point, we in academia cannot do the manufacturing that's necessary, but by then, you have de-risked the project to hand it over to a commercial entity, either to own it or to do it as contracts.

ZIERLER: Maybe it's a naïve question, but why are HIV therapies not profitable for large pharmaceutical companies?

HO: Oh, they are profitable, because there is a market in America and in rich countries for HIV, because there are millions of Americans and Europeans and Japanese who are infected. So there is a market, and the companies make good money in the rich countries. But for the developing countries, they make essentially very little, because they need to provide it at near cost to the developing world. If you turn your attention to TB and malaria, it's totally different, because there's not much of a market in the developed world, whereas the developing world has most of the disease burden. HIV happens to cover both parts of the rich and poor world.

ZIERLER: Of course before you were consumed with the COVID crisis, previously over the past roughly 10 to 15 years, I understand that your research has emphasized a prophylactic strategy to HIV infection, meaning, if I understand correctly, blocking transmission as opposed to dealing with it retroactively. What does that mean, a prophylactic strategy against HIV?

HO: The primary example would be to develop a vaccine that prevents HIV infection, but no one has been successful so far. While researching that, you could ask the question, "What's a good alternative for prevention?" What has really gained momentum is the use of drugs as prevention. The drugs are used to treat, but you can also use them to prevent. That's called pre-exposure prophylaxis, or PrEP. PrEP has really taken root. For high-risk individuals who may be engaged in high-risk sexual activity, PrEP has worked very well with efficacy greater than 90% in blocking HIV acquisition. That's one example of a prophylactic. We worked on a drug together with a company that would be long-acting, so if you could inject it and it would last in the system for a month. Now, instead of taking a pill every night, you could get one injection every two months and you're protected. So there's now a drug called cabotegravir that does exactly that, and the results are somewhat better than taking a pill a day.

That's another prophylactic approach that is working well. Monoclonal antibodies is another way. Instead of using vaccine to raise the antibody, you could make the antibody and give it and have it in the system for a few months, and that would prevent—hopefully; this hasn't been approved yet—but the hope is that would prevent HIV infection. While that hasn't worked for HIV, that has worked for COVID. Let's say you have an immunocompromised individual who doesn't respond to vaccines very well. You could give them passively administered antibodies, and that could protect. An example of that has already occurred in the setting of COVID.

ZIERLER: Looking at PrEP and other prophylactic approaches, what are some of the obvious public health challenges simply in getting the right treatments to the right people at the right time?

HO: The obstacles are economics, logistics, and sometimes the lack of political will. In certain countries, the high-risk individuals, let's say gay men, are considered a fringe population, and therefore the governmental commitment to do something to protect them is deficient. In a lot of countries, it's a poor healthcare infrastructure. You need a certain amount of healthcare infrastructure to diagnose patients, to give advice, and then to administer the pills on a regular basis, and to track these people. Then all that requires sufficient amount of money to support the programs. So it's a combination of those things that preclude us from widely applying these measures that work. If these issues could be overcome, we could potentially shut down the continued spread of HIV. We're still seeing over a million new cases a year, and that is now completely preventable.

ZIERLER: This question might be a bit far afield, but with all of the excitement around quantum computing and the possibilities that might have in a pharmaceutical context, simply for their ability to simulate in ways that classical computing cannot, given that an HIV vaccine remains elusive, do you see a scenario in which quantum computation might lead to positive developments in creating an HIV vaccine?

HO: I think I remain hopeful, but if I see something very obvious that would lead to a protective vaccine, we'd be working on it. [laughs] Quantum computing is not our area of expertise, so we're relying for—we see some results that are promising. The use of quantum computing and artificial intelligence applied to optimizing protein engineering and antibody engineering is certainly extremely exciting, but we're waiting for real concrete results. It may come tomorrow, for all we know. But if there's anything obvious that we should be taking advantage of, we would be doing it.

ZIERLER: As you well know, pandemic preparation was a pillar in the Obama administration's national security policy planning. Were you aware of the seriousness with which Obama approached pandemics, and were you alarmed when the Trump administration before COVID downgraded these preparations?

HO: Yeah. For those of us who think about these things and we follow it—it was probably totally silent to the general public, but yeah. Under Obama, Ron Klein, now Biden's chief of staff had done a lot in pandemic preparedness. There were position papers. There was a lot of stockpiling and preparation. Certainly quietly we were aware of the fact that the Trump administration did not give priority to this aspect and was undoing—let's face it; Trump wanted to undo a lot of things Obama did, not limited to pandemic preparedness. This was another one that was bad for the country, and certainly we know that in retrospect, once COVID hit us.

ZIERLER: What was the decision-making in joining the Aaron Diamond AIDS Research Center with Columbia University?

HO: It took some time, but it was born out of necessity, and that was because we were occupying 40,000 square feet of laboratory space in a building that was provided to us essentially for free by the city of New York. Then, a few years prior to our move, New York City actually threatened to sell that building and turn it into a commercial building, and so we had to look for a new home. Forty-thousand square feet was difficult to come by. We were part of Rockefeller University, but Rockefeller, as you may know, is a very small institution that could not provide us that 40,000 square feet. We started to look for other private space, and that's at a point where Columbia stepped in. Columbia had created a new campus at a place called Manhattanville. That's somewhere between the main Columbia campus and the medical campus. By creating that new campus, initially for neuroscience, all the Columbia neuroscientists moved out of the Columbia Medical Center. Then, at the right time, they had a lot of space freed up, and they said, "What about you joining us?" So we were being acquired by Columbia.

We were prior to that an autonomous entity, so it took several years of negotiation for all that to happen. That solved our space problem. Then we switched the academic affiliation from Rockefeller to Columbia. Our assets were acquired by Columbia, and we all became a Columbia faculty member. Our center retained its name. We wanted to keep that legacy. Then we moved in January of 2020 into the Columbia campus, as the pandemic was just emerging. It was perfect timing, and we have been at Columbia doing largely COVID work and very little HIV work.

ZIERLER: Have you retained academic affiliations with NYU or Rockefeller in the course of this transition?

HO: No, no, we had to sever those relationships in order to set up the new one with Columbia.

ZIERLER: Beyond the real estate solution, what has the partnership with Columbia allowed you to do?

HO: Actually it has been great for our COVID effort. As you may know, Rockefeller is a very basic research organization, in many ways just like Caltech, except focused only on life science. Caltech goes way beyond life science. But it doesn't have a medical center, so it's harder to do clinically related research from Rockefeller than from Columbia. At the peak of COVID in 2020, the hospital outside my window here had 600 COVID patients. It was very easy for us to study patient material, to figure out who has the best antibody from whom to clone the monoclonal antibodies, for example. We did that very nicely, seamlessly. Lots of clinical colleagues that could help us out with clinical material. Also, the other thing is, as part of the real estate deal, Columbia built a brand-new biosafety containment laboratory for our HIV work, which we then utilized for our COVID research. That was great. So, many things just fortuitously turned out really well for us.

ZIERLER: It sounds like your work is not operating in an island within Columbia. It's really important to integrate within the overall health research that's happening at Columbia.

HO: Absolutely. I just talked about the large clinical component, but in addition, Columbia Medical Center and Columbia Medical School, much, much larger than Rockefeller. Rockefeller has 70 labs. Columbia has many more labs, and many more researchers. We were able to engage many other groups to collaborate with us and get the work done very, very quickly, as part of the pandemic response.

ZIERLER: A social, even a policy question: when COVID began, one particularly worrisome development at the beginning of the pandemic was discrimination and even violence that Asian Americans experienced. Between your stature and your personal background, did you ever see opportunity to speak out? Did you ever feel compelled to criticize the Trump administration's response when he said things like "Kung Flu," for example?

HO: Yes, of course I spoke out, but I don't have the same large megaphone he has. I spoke out in my own way, in my community, my school, my group, and occasionally on television when I'm asked to comment. I think to blame China, to blame Chinese Americans for this is not helpful. It's not warranted. It only leads to tension and conflict. As a result of that, you see violence directed at Asian Americans. It's still happening today. I have a doctor friend, he's actually Chinese American, but he's six-foot-four, and he has people chasing him and saying nasty things about the pandemic and Asian Americans. In New York, we see a lot of violence directed to Asian women. You speak up, but I don't know how much impact I'm going to have on that front. I've spoken to Asian American scientific organizations, lending my voice to the effort to destigmatize and to confront discrimination, all on a pretty small scale, I would say. But our previous president did a lot of harm along that line, and that effect is lingering.

The other issue, not so much related to the pandemic, is the China Initiative that's launched under the Trump administration by Jeff Sessions. That is highly discriminatory toward not only scientists that came from China, but Chinese American scientists, almost by association, are on some sort of watch list and are pursued for criminal activities when they have violated issues of confidentiality and non-disclosure. They're infractions, no doubt, but they're minor. They're certainly non-criminal, and some of them are non-intentional. We see a lot of that. I would just take this opportunity to say that I have served the country I think nicely for two different pandemics, HIV and COVID, and I'm on some sort of watch list by the FBI. I don't know why. I don't take money from China. I only help China addressing HIV and SARS and COVID. I have all sorts of honorary roles there, but I don't take money, but I'm on some sort of watch list. I come back from a trip in Europe, and I'm detained, interrogated, searched. It's just wrong. I reached out to the White House through Tony Fauci, and to the NIH and to the General Counsel at Columbia. This is probably the first time I've felt this level of discrimination as an Asian American. Previously, I may have suspected discrimination here and there, but this is an overt example.

ZIERLER: It's scary for us all that this is where things are in 2022.

HO: Yeah. I know that Biden just reversed course on the China Initiative, but I don't know how quickly things will get turned around. I have another trip coming next month. I'll see if I'm detained and interrogated when I come back.

ZIERLER: Perhaps in happier news, bringing our conversation right up to the present, it's looking now that we're thankfully getting beyond the omicron wave and people are talking about getting back to quote-unquote "normal." Mask mandates are dropping alongside case counts. Of course we've been here before. Right now, what are you looking for to see if COVID finally becomes endemic, and what might suggest instead that we're simply headed toward yet another mutant strain and a resulting infection wave?

HO: I don't know what the future has in store for us. The one thing I would worry about would be a variant that's substantially different from the current one. We see sub-variants emerging, so omicron now has BA.1, BA.1.1, BA.2. The original, BA.1, is gradually being replaced in this country by BA1.1, and then BA.2 globally is creeping up. That's concerning. These are not drastically different from the original omicron, so I'm not too worried about that, but I worry about one that is totally unexpected. In November, we didn't know about omicron. By after Thanksgiving, we knew it was a problem. And it could pop up any day. We said the next variant would be the son of delta. That turned out not to be the truth. Because delta was so dominant. Before that, alpha was so dominant, and we thought the next variant would be son of alpha, and that wasn't the case. So I wouldn't say son of omicron would be the next variant. It could be something totally unexpected. That's what history over the last 18 months has taught us. It could come from anywhere where the virus is replicating, and that's almost everywhere, although not at a high level presently. Omicron emerged at low level in some part of southern Africa. That's what I would worry about.

The other thing I would worry about is, aside from Africa and some poorer countries where the vaccination rates are low, we have 1.4 billion people in China that essentially their sole strategy is to lock down. These are susceptible individuals, and they've been vaccinated with vaccines that are really poor by comparison to our mRNA vaccines. They cannot continue the zero-COVID policy for much longer without taking a huge economic toll. Once they open up, the omicron-like virus is going to spread like wildfire, unless they buy the Western vaccines and vaccinate quickly. But national pride is dominating the thinking right now, and they basically don't want to say, "Our vaccines are inferior." I worry a lot about that. If omicron or another variant rages through China, it's going to produce a new variant that will come back and threaten us. So, a number of things I worry about. But I think, as you said, we have some good news right now. Cases are way down and people are more relaxed, and life seemingly is becoming normalized once again. That's all good. But as you said, we felt that way in early November of 2021, and then overnight, we were saddened by the news of omicron.

ZIERLER: Whether it's next month, next year, or next decade, hopefully at some point, at least in the developed world, COVID will be behind us or something that we can live with and manage somewhat easily. To what extent for the Global South or the developing world are you concerned that COVID is going to follow a similar trajectory as HIV, where for the long term, decades into the future, COVID can continue to wreak havoc in communities that are not vaccinated and don't have the public health infrastructure to deal with it?

HO: I think the poorer regions of the world will have low vaccination rates, and the virus will find those who are not vaccinated sooner or later. It's at a low prevalence, so it may not infect them readily right now, but given enough time, the virus will catch the susceptible. But 98% of the infected individuals will overcome and survive. There will be blips in higher death rates and increased hospitalization, hopefully not in dramatic ways, and then herd immunity throughout the globe will continue to build, if not by vaccination but then by infection. In a few years' time, much of the world would have developed some type of immunity, either through vaccination or through infection. The severity of disease will be way down, and death and hospitalization will be way down as well. That's not too different from flu. We will get there at some point. As you said, we don't know whether that's months from now or years from now. I don't believe the situation will be as bad as the past couple years. But the public pretty much as of today or very, very soon, has determined the pandemic is over, at least in America and in Western Europe. This is reminiscent of what we read about the Great Influenza pandemic; it's over when the public says it's over, not when the CDC says that it's over. There, we witness another wave or two of serious infections, even after the public declared the pandemic over.

ZIERLER: Now that things are looking good, at least for the time being, with COVID, given that it has been an all-hands-on-deck endeavor for you and your group researching COVID, to what extent has HIV research been back-burnered because of COVID, and in what ways long-term might it be strengthened simply because of all of the resources that are now being poured into virology?

HO: I think for us, HIV research was completely stopped throughout 2020 and largely stopped throughout 2021. We're just initiating a number of projects on HIV in 2022. Our majority of effort is still focused on COVID simply because everything related to COVID is urgent, extremely urgent. I think the COVID experience has been helpful, in that we know we can do things very fast while keeping the quality of the work high. The whole nation has discovered that. Why does drug discovery and development have to take ten years when you can do it in a year, if you want to? It's beginning to change the paradigm and change our thinking. People used to just be very complacent—"Ah, you develop a product; it will take a decade." Well, look at how many products were all developed within the course of a year—several vaccines, several monoclonals, several drugs. It's amazing. So it has changed our thinking. And some of the technologies, like the mRNA technology, it was developed long ago, but then put into action, and now we know we can adapt it very quickly. So these past couple of years will help our HIV effort.

ZIERLER: To go back to an earlier conversation where you were explaining the special treatment that Magic Johnson got when he was infected with HIV, and how we can understand how beautifully well he has done in intervening years, how would you compare Magic Johnson's treatment to when President Trump got COVID, obviously before he was vaccinated. Given all the comorbidities he clearly had, him coming out so well, what does that tell about COVID and special treatment for the unvaccinated?

HO: Magic Johnson benefited from early combination antiretroviral therapy probably one year ahead of the general public. In Donald Trump's case, he benefited from the monoclonal antibody therapy about a few months before the general public had access. Fortunately for both of them, they did well. Magic Johnson, as we discussed, was immunocompromised by the time he was diagnosed, and 30-some years later, he's doing great. Donald Trump we now know was severely ill from COVID, approaching respiratory failure, and we know that he's at least got several major risk factors, one being his age and second being his weight status. He was on the decline. We know that the antibodies he received would lower hospitalization and death rate by 90%, so there's very little doubt he benefited from that intervention early. Who knows what would have happened otherwise.

ZIERLER: As I'm sure you've seen, there have been some recent prestigious studies claiming conclusively that COVID originated in the wet market. Are you satisfied at this point that this is settled history, and do you think this is a positive development given all the mistrust that has developed between the U.S. and China over the supposed lab leak theory?

HO: I think the recent studies continue to support an intermediary animal source for the COVID outbreak. Personally—you say, "Is it completely water-tight?" I would say not. It's consistent with that, so it's supportive evidence, but it's not definitive in my view. We need to continue to pursue this line of research to find out exactly what happened, but without full cooperation from the Chinese side, that's not likely to happen. At least for me, I never thought this was a virus that was engineered by humans, or intentionally or accidentally leaked out of the lab. I never thought that was a serious possibility. Because scientists, if you should discover a new virus, you report it, you share that information. That's how you get your credit. There's no reason why that lab would have held that virus without reporting it. I think it's good to have these additional studies come out, but we should continue to ask questions and to pursue it.

ZIERLER: For the last part of our talk, I'd like to ask a few broadly retrospective questions, some even that borderline a little bit even on philosophy. First, your approach, your career trajectory in pursuing an MD, knowing that you wanted to work in a research environment, to the extent that you interact with young people who might seek advice on their career trajectory, is the approach that you took one that you would suggest for others? In other words, in this day and age, is going for the MD while wanting to pursue research still the way to do it?

HO: For me, it was the right choice. For others, I don't necessarily think—I think you need training to acquire the skills that are necessary to do the job. The actual degree probably doesn't matter as much. I see PhDs involved in clinical research; they learn on the job. I see MDs doing a lot of basic research. Again, learning on the job. So the degree doesn't matter as much as the training itself. You go acquire the skills you need. I have people working with me who are PhDs, and I have MDs, and I don't think about their degree when I assign projects. I think it's a matter of what skills you have.

ZIERLER: For all of your admirers out there who wonder how you do it all, I wonder if you can talk a little bit about some of the work habits that you've developed that are most efficacious, even prosaic things like delegation, time management, multitasking. How do you get it all done?

HO: I think first you have to like what you do. The dedication will only follow when you have the passion. As advice to younger folks, younger scientists or other youngsters, I say, "You have to pursue your passion, otherwise you will not put in the effort, and it becomes a chore. You should love what you do." That is the case for me. I also tell them there are a lot of smart people out there. People who come to work with me are all smart. But if you're not tenacious, you're not dedicated, you're not going to succeed, because those who rise to the top are generally both smart and hard-working, and very committed. I also love to tell my students and postdocs a well-known Japanese proverb. You really need to have both the intellect and the actual hard work. The proverb goes like, "Vision without action is a dream. Action without vision is a nightmare."

ZIERLER: [laughs]

HO: I see all types in the lab, the people who are doer-doer-doer but that sometimes it is without proper direction. That's a nightmare. Then there are those who have got beautiful vision but they sit around all day not dedicated to the work. It's like they're daydreaming. But those who really are successful could have the vision followed by the action to execute.

ZIERLER: We talked about TIME magazine. Beyond that, you've been awarded and honored in so many different ways, certainly more than we'd be able to talk about now. What are the most meaningful ways that you have been recognized, that are personally significant to you?

HO: Probably none of those awards. I think I've said this to certain people doing interviews: the most meaningful ones are coming from total strangers. I'm sitting on a plane, and a flight attendant recognizes my name and perhaps my face and says, "Thank you for all the work you've done. You saved my life." That is probably more significant than receiving this award, that prize, because it's very personal. I've gotten more than my share of such recognition from strangers, and that's meant a lot to me.

ZIERLER: At awards ceremonies, you have always been so generous in emphasizing that your work is the result of a team effort; that it's not just you, there's a whole team of researchers there. In that vein, who are some of the real unsung heroes, in the lab, in government, in research, in policy, that really make these breakthroughs happen both on the fundamental and the translational side?

HO: There are just so, so many of them. For my recognition, let's say for the work that we did on combination antiretroviral therapy, I have so many colleagues to give credit to. It took a lot of people in the lab to do the mundane measurements of viral load that allow us to understand HIV dynamics that led to the formulation of the strategy. Those are my colleagues who are on those papers but are underrecognized. The clinicians who administered the drugs and saw the patients, the research patients on a daily basis, they are also underrecognized. But even going back before that, the folks who synthesized various chemical analogs to come up with the compounds, the chemists, they are underrecognized. Without their effort, there would never be the protease inhibitor, the polymerase inhibitors, et cetera. It really took a whole community to make progress. When I was recognized by TIME magazine, I knew, and they said so as well, that I was being picked out as a symbol to represent the progress made by the scientific community. This is why I like to quote Isaac Newton when he said, "If I can see further, it's because I stand on the shoulders of giants." I stood on the work of many, many others in making an incremental contribution that then led to the breakthrough.

ZIERLER: For my last question, I'd like to end on something of a philosophical note. If you step back and survey your career from the beginning of when you started to think deeply about immunology and virology, all that we've learned in the past 50 years, all of the way that your research and the research of your colleagues have contributed to all that we've learned—if we go back to Socrates, who tells us that the more we know about something, the more we know how little we know, when you look at a virus, what strikes you about how deeply we understand it, and through that understanding, what strikes you about how truly little we actually understand?

HO: I always advise my younger colleagues to be aware of what we don't know, how little we know. That old saying by Socrates is so, so true. We now know about COVID-19 quite a bit, although still a lot more to learn, but that's causing us to think about what other pathogens are out there. We haven't surveyed the animal species enough. There's so many more genes to SARS-CoV-2 than HIV. We understood pretty much every gene function of HIV. We don't understand the function of most of the SARS-CoV-2 genes. We sort of know what the virus does in general, but how each gene mediates its action is largely unknown. That applies to only one virus. What about all the viruses we don't know? It's pretty humbling.

Scientifically, the younger colleagues have a tendency to say, "Oh, we know this, therefore this ought to be the path forward." But I'd like to tell them that, "Well, there's a lot more we don't know, and you're making a decision based on the fact that the light is shining on this particular spot only, whereas the rest remains dark, and that decision, while it may sound very logical based on the known facts, but you need to account for the fact that there's a vast amount of data missing." That would prompt you to be more humble and less definitive about the approach to be taken.

ZIERLER: "Keep your eyes open" is what it sounds like you're saying.

HO: Yeah.

ZIERLER: David, it has been a tremendous honor spending all of this time with you. You're a real point of pride for Caltech. So many people here are thrilled that we were able to do this. I'd like to thank you so much.

HO: Thank you.