CBS

Interview with Dr. David Ho

Posted on Nov 30, 2011 09:00pm


Dr. David Ho
CEO of the Aaron Diamond AIDS Research Center, Professor at Rockefeller University Medical School and Head of the China AIDS Initiative

CBS CARES: How did the China AIDS Initiative come about and what are your objectives?

DR. HO: Well, we wanted to link together a number of organizations to help address the epidemic in China. We realized that the only effective way to approach this is in a comprehensive manner. This is because you cannot just address HIV as a biomedical problem. It comes with all sorts of attendant issues. You have to take on the issues of stigma and discrimination. You also have to address the human rights and legal aspects and the many other social issues that come along with HIV/AIDS. There's not one organization that has the necessary skills to do it all.

We increasingly realized that we have to link together groups that complement one another. We started to do that with some American organizations that have an interest in China. Very importantly, we also have to have local partners in China. That's why we have partnered with the Ministry of Health, a number of bureaus of health in the provinces, as well as universities and Chinese academies involved in this area.

CBS CARES: Did the Chinese government approach you or did you approach them?

DR. HO: No, we actually were rather proactive. The Ministry of Health initially signed an agreement with our institution on vaccine development. But we have substantially broadened that relationship over time, including partnering with the Chinese Academy of Medical Sciences, which is equivalent to the National Institutes of Health in the United States. Without endorsement by the Chinese government, it would be difficult to have an effective program in China.

CBS CARES: How did your PSA with Magic Johnson and Yao Ming come about?

DR. HO: It came when we were trying to get the Chinese government to take stock of the situation and support the many things we wish to do in China on HIV/AIDS. In 2003, we had engineered a big event that involved President Clinton at Tsinghua University in Beijing. That event made a big impact in my view because it allowed Clinton to send messages directly to the Chinese public. It also privately allowed him to speak to a number of the highest leaders. President Clinton said: "I'm here on a health mission, not on foreign policy." That shocked the Chinese leadership, to be frank.

So, I think those messages got through. We cannot take the whole credit. There are a lot of other organizations that have been working on advocacy for a long time. The collective outcome is that only a few weeks after President Clinton's visit the Chinese policy on AIDS took a dramatic turn in the right direction.

We want to sustain the momentum and that includes doing something that is more focused on the public. So we thought about using high profile figures. Magic Johnson has been under my care since before his public announcement. He was incredibly supportive about doing something to support our efforts. And since it's the China AIDS Initiative, we thought about a Chinese celebrity and Yao Ming was the obvious. He has such a high profile here, but you should see what he's like in China! I thought the combination was particularly powerful because we could put an American and a Chinese together, and a high profile infected person and an uninfected person together. I thought the dynamics between the two would be very powerful and they could effectively promote awareness as well as prevention and non-discrimination. So, Magic sent a message to Yao and David Stern, the NBA Commissioner, said he was very much behind it...and it happened.

CBS CARES: How informed are most Chinese people about AIDS?

DR. HO: In some surveys that have been done, half of the Chinese don't know the basic aspects about HIV/AIDS. That is simply not acceptable for a global plague that is also affecting China. We simply need to raise awareness and the PSA is part of that. Of course, there's self-interest here because we're trying to get a lot of things done in China. Unless we can make advances in correcting the mindset of the Chinese public our tasks will be so much more difficult.

CBS CARES: The AIDS epidemic in China has been described as a grave threat to both China and the world. Why is AIDS in China a threat to the world?

DR. HO: AIDS in China is part of the second wave of the AIDS epidemic--one that threatens China, India, Russia, among others. This wave will add a tremendous number of new AIDS cases in addition to what we already have around the globe today.

We know that China has had an epidemic of HIV/AIDS since 1989, beginning first in drug users and then followed by an epidemic that was spread because of certain blood selling practices in the central region of China. The World Health Organization estimates that there may be somewhere between 800,000 and a million infections in that country. Given the trajectory of the rising caseload, however, it is likely to hit the 10 million mark by the end of the decade. Obviously, that will add a tremendous load to the global pandemic.

CBS CARES: How accurate is the estimate of current infections in China? In a country with such a large population and 800 million people living in rural areas, how are they able to come up with an accurate number of infections?

DR. HO: In my view, these estimates of infections are not very accurate. Given that until fairly recently there were only 60,000 Chinese who had been confirmed HIV positive. That's, of course, a small number compared to the new estimate of 800,000 to a million, so it cannot be all that accurate. Nevertheless, whether it's half a million or two and a half million, you probably would approach it more or less the same way. I should also point out that the Chinese government recently has launched wide scale testing in several of the key provinces. It would not surprise me, if six months from now or a year from now, we would have numbers that are much more reliable

CBS CARES: If your China AIDS project is successful, to what extent do you think that you can reduce the 10 million projected infections by 2010?

DR. HO:With an epidemic, the sooner we make an impact, the greater that impact will be. So, ambitiously, we'd like to affect the outcome by four or five fold if that's possible, but that depends on the actual number of current infections.

CBS CARES: When will it be too late to intervene in China?

DR. HO: I think we cannot afford to sit around for another year or two without many intervention programs.

CBS CARES: Why do you think you can be successful in stemming the AIDS crisis in China when it has been so difficult to do so in various other countries?

DR. HO: Well, in some ways, China is still a developing country, but it is not a typical developing country. In China, there are maybe 300-400 million people who are better off and have more resources than others in the country. If we could convince that portion to take stock of this situation, then the haves in China could help the have-nots. The other factor is the Chinese way of doing things. If you could convince the Chinese government that this is serious and could threaten its stability or economic future then it can mobilize very effectively as we witnessed with SARS in 2003. If you look at the initial course of SARS, China made a terrible mistake. That was an embarrassment in front of the rest of the world. But once it reversed course and took the right path, it did so highly effectively and shocked the international community in how quickly it brought SARS under control. In that respect, we think that we need to do our advocacy work. If the Chinese government could take on more and more of the responsibility, it will make a major contribution to curtailing the spread of this virus in the country.

CBS CARES: Is there health insurance in China?

DR. HO: For a limited number of people living in the richer, coastal region, there is the beginning of the private health insurance. But, the Chinese epidemic is largely a rural one, mainly affecting the poor who do not have access to health care or health insurance.

CBS CARES: Do you believe that generic drugs should be used in China?

DR. HO: Well, they are being used. China already makes four generic drugs. Unfortunately, these do not make a good combination. You would have to add a drug like 3TC from America to boost the power and effectiveness of drug regimens.

Until recently, China was using strictly generics that are made according to World Trade Organization rules so they're not in violation of any intellectual property laws. They are gearing up to make more, but they're waiting for some of the patents to expire and for the government to work out deals with multi-national pharmaceutical companies.

CBS CARES: One projection is that by 2010 the number of worldwide HIV infections will be 105 million. Five million were infected last year alone…is it true that last year marked the largest number of infections in any year since the start of the AIDS pandemic?

DR. HO: That's right. And some feel that the numbers are more dire than the projected 105 million. India alone could have 25 million infected by 2010 and you have to add the 10 million projected for China…that is, if nothing dramatic is done in these countries.

CBS CARES: Would you also say that the spread of the AIDS pandemic to countries like China, India and Russia increases the threat of AIDS to the global economy?

DR. HO: Yes, I think it is already a burden, but hitting these major countries you mentioned would increase the economic burden a great deal. We all know that China and India are becoming increasingly economically important to the world. China, for example, is a manufacturing juggernaut. So, if the epidemic were to become much more diffuse throughout China and affect, say, the coastal provinces, then it would be an even greater threat.

CBS CARES: Well, if after more than 20 years of the pandemic, AIDS is spreading faster than ever…do you think that the disease is winning this war, so far?

DR. HO: As you know, there's been tremendous scientific progress made on HIV. But the progress has been most meaningful for people living in developed countries, particularly the patients in those countries. If you look at the epidemic curve in Africa or in South Asia, it's as if all the advances have made no difference. I think that, in realizing this inequity, more and more agencies are trying to close the gap and deliver treatment. And, also importantly, there are more prevention efforts in the countries where the virus is spreading most rapidly. I don't think we will change the global pandemic until we begin to address prevention in a very serious way, of course continuing to do so in Africa, but also in these so-called second wave countries like China, India and Russia.

CBS CARES: Can you tell us about the vaccine aspect of your partnership with China?

DR. HO: The vaccine is a much longer-term effort. We made the vaccines here and are doing human testing in New York. At some point, we would like to take it to China and do the subsequent clinical trials there.

CBS CARES: From your experience, do you believe that there will be an effective vaccine and/or cure for HIV in our lifetime? Is that an achievable objective?

DR. HO: I guess if we didn't think that was possible we would not be working in this field. Certainly for a vaccine, if we felt that it was futile, we'd be better off concentrating on another project. It's clear from the animal experiments that it is possible to achieve a reduction of progressive HIV infections using the kind of strategies that we're using.

We're reasonably optimistic that we could get at least a partially effective vaccine. And, if it's not 100 percent effective, we should not make perfection the enemy of the good. If there is anything that would help slow down this epidemic, we should push ahead and others can come along and improve upon the first generation vaccine. On your question about a cure, it's not within reach right now, even though we have very good therapies that control HIV very well and people are living very productive lives in the U.S. and Europe on treatment. But HIV is still not cured ffrom those people. The virus is hiding out in small amounts in certain cells. We have yet to come up with strategies to purge those elements from the infected person.

CBS CARES: Your organization discovered the CCR5 receptor on the CD4 immune cell, which is one of the doors for HIV entry and infection of those CD4 cells, right?

DR. HO: Scientists in our institute discovered it, yes.

CBS CARES: Since the CCR5 receptor is part of the process by which HIV infects cells, does your vaccine research include how that receptor can be genetically adjusted to resist entry by HIV?

DR. HO: Well, that knowledge is very useful, but we're actually not manipulating the CCR5 molecule. We are just manipulating the viral proteins to present those proteins to the immune system. And you can say the CCR5 molecule might be very important in that process. What you're suggesting would be more akin to gene therapy. That is being attempted by some other groups but we're not involved in that directly.

CBS CARES: What do you view as the most promising vaccines candidates that are currently in development?

DR. HO: Well, the ones that are being worked on right now in terms of concrete development of vaccine candidates are all in one way or another very close to the strategies that we're taking. One is to use what's called DNA plasmids or viral vectors. These simply are vehicles to deliver HIV genes safely into humans or into animals. And then once delivered into the host, HIV proteins would be made in the host. Of course, this won't be infectious, but the immune system will see those proteins as if there's HIV infection and therefore begin to mount an immune response. So when the real virus comes in, it could be blocked.

CBS CARES: Would this be an antibody response?

DR. HO: Antibodies, but the tough part is that antibodies do not work very well against HIV. HIV has evolved to have a shield. If you're a believer in Star Wars, HIV has that force that protects it, so the antibodies sort of bounce off the shield. That shield actually consists of certain structural elements like carbohydrates. So it's actually very, very clever how this small virus has evolved to be so challenging for us.

CBS CARES: So these vaccines will really result in a cellular immune response?

DR. HO: Yes, the current approaches rely heavily on the cellular responses. I'm impressed with all these questions…you must be working on the CBS program CSI!

CBS CARES: So you watch CSI?

DR. HO: I do sometimes watch it.

CBS CARES: Is it true that embryonic stem cells cannot be infected with HIV and do you see stem cell research potentially resulting in a vaccine, a cure for AIDS?

DR. HO: Just the initial embryonic stem cells don't have the necessary receptor to be infected. When you then go down a few steps to what is called the hematapoetic stem cell, there's some controversy about whether or not it has the necessary receptor. That cell is what we call CD34 Positive. It may have the receptor and some groups have reported infection in that cell population. But this is not an area that's clear-cut right now. In terms of the use of embryonic stem cells or any form of stem cell, I think it should be worked on because many of the gene therapy approaches depend on having either the true embryonic stem cell or the hematapoetic progenitor cell. If we could engineer into that cell a molecule that will resist HIV, then the progeny cells, the daughter cells, would all be resistant to HIV. You could then take a person whose immune system has been wiped out and repopulate their T cells by the injection of such engineered embryonic or hematapoetic progenitor cells. This could repopulate this T cell population with cells that are resistant to HIV.

CBS CARES: Could there be any use for adult stem cells, for example by genetically engineering them?

DR. HO: There could be. I just think that embryonic stem cells hold greater promise--they're likely to divide and repopulate more while the adult cells would have a more limited life span.

CBS CARES: When you came up with the idea of the triple drug cocktail, did you have a "Eureka" moment? Or was it a gradual progression of conclusions from research?

DR. HO: The idea of using multiple drugs together was not a "Eureka" moment because, if you think about it, that is rather simple and there is a great deal of precedent in medicine to use multiple drugs to treat one single disease. The "Eureka" moment really came from studies that were done a couple years before to elucidate the dynamics of HIV replication in infected people. In early 1994 we showed that the virus replicates continuously at enormously high rates. Once we started to realize that this virus is not quiescent at all, it's highly dynamic, it's constantly doing its thing and mutating and the body is constantly fighting back, we quantified that process.

If you throw one drug at HIV at a time, it is sure to escape from that drug. If you then come with a second drug, it's sure to escape from the
second drug, the same for the third and fourth. So that if you do things sequentially, you are doomed to fail. But, if you use the strategy of throwing multiple drugs at the same time, HIV may evade drug A, but it also has to evade drug B and C at the same time. If one drug doesn't get it, the other drugs should. And so the "Eureka" moment really came early on when we realized we had the data in our hands from a clinical trial that showed how quickly the virus turned over when we used a protease inhibitor. While my colleagues and I celebrated the success of that protease inhibitor in early 1994, within that data set, we had the answer about the dynamics of HIV replication. Subsequently, in 1995, we went on to do this with a combination of drugs and were the first to demonstrate that our thoughts were indeed correct.

CBS CARES: When you developed the triple drug cocktail, which suppressed HIV viral loads in blood to undetectable levels, did you feel for a while that you had actually eliminated the virus and cured the disease?

DR. HO: I was never that optimistic. What was exciting back in '95 when we first saw these results, and to some extent in '96, is that we knew we had shut down the virus in ways that were obviously new. Previously, the drugs we had were unable to achieve those kinds of results. By then we had already worked with the virus for over 12 years and we knew how tough HIV is. We were able to project that the known compartments of HIV would decay out in two to three years, but the caution was that those are only the known compartments. The question remained, "What about the unknown compartments?" And true to form, science showed us that there are additional compartments.

CBS CARES: By the compartments where it turned out that HIV was hiding, you mean resting CD4 cells, lymph nodes and organs?

DR. HO: Yes.

CBS CARES: Is any research currently being done to try and flush out HIV from those compartments so that it can be killed by the antiretroviral drugs?

DR. HO: Yes, but not a lot of research because we know how tough that task is. Just one example--you mentioned the resting CD4 cells. Well, we actually know how to turn on the T cell, but we don't know how to turn it on safely. If we go with a brute force approach and turn on lots and lots of T cells in the body, the outcome would be a toxic shock syndrome for the patient. What we need is to be able to turn on the T cells selectively…a little bit at a time…so that the person is not hurt by the process. And that is a novel area of medicine. We have some ideas and these ideas could be safely tested in animal models before going to humans. This is an area that I think is quite challenging, so I'm not sure I'd want to say there will be a cure in 10 years or 15 years. I just don't know.

CBS CARES: Earlier you were talking about how effective the drugs are and this is great news, but what do you say to young people that would say to you that it's not a big deal to get HIV and that there are already good drugs to control the disease as if it's like diabetes?

DR. HO: You know, while we should celebrate the successes in treating HIV, the young people should realize that this still is a lethal disease in most parts of the world. Even if you're fortunate enough to be in the United States when you contract HIV, the therapy is not so straight forward. It could affect your life a great deal. There are side effects. You know, we only have less than eight years of experience with these drugs. What are the long-term consequences of taking three or sometimes four medicines a day for indefinite period? We simply don't know that. We are realizing that there are late consequences to these treatments. You've probably heard about lipodystrophy. That is a certain loss of fat tissue from the face and limbs and then the fat is redistributed to other parts.

CBS CARES: Except for the drug D4T, there seems to be some debate now on which drugs are the culprits in causing lipodystrophy. Is this known and does HIV itself cause lipodystrophy?

DR. HO: Some of lipodystrophy could be caused by HIV itself, but there's no doubt that certain drug regimens predispose people to lipodystrophy more than others. The D4T you mentioned is certainly one of those. Initially, it was actually attributed to protease inhibitors, but I don't think that's strictly true. These consequences could affect the person taking the drug a great deal so that they actually prefer to stop the medications. So HIV treatment is not an easy thing to deal with and it goes on indefinitely. We all have trouble trying to take a few pills for a strep throat or something else for a week or 10 days. Think about doing that for the rest of one's life.

CBS CARES: What good news can you give to readers of this interview who are living with HIV/AIDS?

DR. HO: The good news is that there are better drugs in the pipeline. We already have 21 drugs in the United States and more are coming. In the future we will have probably more in the newer classes. Currently there is only one drug that is considered an entry inhibitor and it's an injection, which patients don't like. But in the future I can see several other drugs in that class that block entry of the virus. I also see another set of drugs that will block another key step in the viral cycle, integrase.

CBS CARES: In what time frame?

DR. HO: Likely in the next five years. And quite importantly, there's some "me-too" drugs...improvements of existing drugs against the same viral targets. They might be important because they might simplify the drug regimen or they may have fewer side effects. So they may not confer an advantage in terms of anti-HIV activity but it could be once a day instead of twice a day therapy. And it could be that they won't have the lipodystrophy side effects.

CBS CARES:Do you think, as HIV drugs become less toxic, that your hit hard and hit early strategy--placing a patient on an aggressive regimen of HIV drugs as soon as they are diagnosed rather than waiting for the immune system to decline--could be revived?

DR. HO: Yes, there is no doubt that what has tempered what I advocated in 1995 has been the drug side effects. I described earlier the dynamic nature of HIV replication. And associated with that is a constant depletion of important cells in the immune system. So why let it continue if you have the capability to shut it down? Now, given our current arsenal, if we shut it down we pay a price--the side effects. Therefore you have to temper your decision. But if the drugs become less and less toxic, and easier and easier to use, it shifts the equation back in the other direction. I have always argued that people are quite happy letting the tank run from full to half tank because they feel that nothing much has happened to them, but you pay the consequences later.

CBS CARES: Do you think that the future of HIV therapy will involve testing to see which drugs are best for an individual patient, based on his or her genetic profile and characteristics of their virus?

DR. HO: I think that specialized genetic testing is in our future. We're not quite there today. There's a movement towards individualized medicine where I could study your virus, understand it better. I could study your genetic factors and make very personal decisions for you as to what is the best treatment strategy for you. There are many biotech companies that have been built with that premise, but I think it's still some years away.

CBS CARES: There seems to be a debate whether HIV should be seen as an immune activating disease or as an immunosuppressant disease. What's your view and do you foresee HIV patients ever being treated with immune modulating or immunosuppressant drugs?

DR. HO: HIV is a fascinating disease. The virus comes in, it replicates in these CD4 T cells, and gradually depletes them. That's the immunosuppressive aspect. But at the same time, you look at the uninfected CD4 T cells or the CD8 T cells, they are activated. So there's a specific immunodeficiency in the context of a generalized activation of the immune system. It's paradoxical, but now pretty well demonstrated. So for this immunosuppressive defect, you want to stop the virus from depleting those important CD4 T cells. At the same time, you want the generalized activation to go away because it is not good.

My colleague here, Marty Markowitz, has a clinical study in patients in the early phase, when they first become infected. He treats them with HIV drugs to block virus replication. Simultaneously, he gives them an immunosuppressive agent, what we call cyclosporine, to tone down the generalized activation and to see if that has a beneficial effect.

CBS CARES: There is some debate on this issue too: does Hepatitis C and HIV co-infection result in a delayed antibody production so that a person in this situation should wait longer for a reliable HIV antibody test?

DR. HO: I'm not sure if we would have data to speak to that. And I haven't read anything that's convincing to me that Hepatitis C slows down creation of HIV antibodies…what's called quot;seroconversion."

CBS CARES: Wangari Maathia, the Kenyan woman who recently won the Nobel Peace Prize, says that HIV was created in a lab by scientists to perpetrate genocide? What would you say in response to that suggestion?

DR. HO: I don't think that's my view. Well, let me clarify that: it is definitely not my view! HIV has so much that science did not know previously. We are still not smart enough to create this virus. And there's ample evidence from studies in chimps, in monkeys, in various primate species in Africa, to tell us that these viruses have been around in those animal populations for a long time. The virus that is causing the global epidemic is closest to that found in a type of chimp found in Central and West Africa.

CBS CARES: HIV was around for decades before it was discovered and diagnosable--and infecting humans during that period. Has anything been learned from that to prevent a reoccurrence with another type of retrovirus?

DR. HO: I think we could pick up anything that is fairly close to these viruses through the current tests. But if you have a virus that's substantially different, I'm not sure we would pick it up. And we know new viruses are constantly emerging. SARS, while different from HIV, is a good example.

The other thing I should mention, going back to your last question, there is a viral evolution clock that ticks at a certain rate. So, we know that HIV's been around for a long time--and in the human population since the 1920's or 1930's, probably at a very low level in Africa. And there is a documented case of HIV infection in a human going back to 1959. So, I don't agree at all with the statement from the Nobel Peace Prize winner.

CBS CARES: Turning to you, is it true that, when you came to the United States from China, you couldn't speak a word of English?

DR. HO: That's true.

CBS CARES: How did you learn English?

DR. HO: The hard way; being thrown in there and told: "Learn!"

CBS CARES: What were your first impressions of American life and culture? Was it different from what you expected?

DR. HO: Well, this was 1965 and I was 12, about to turn 13. My world totally changed. I was used to walking and bicycling everywhere in Taiwan. I may have ridden in a car twice. We did not have a TV set in Taiwan and all of a sudden, there was a TV set in our home. I remember, in Taiwan, my mother went to the local market every day and brought home what we were going to eat that day. All of a sudden, we were in this giant supermarket in Los Angeles, where you push the cart around and you load up for the next week or a few weeks. It was just very different. But the most traumatizing thing was not being able to communicate. I went from a fairly good student to probably the dumbest kid in the class, overnight.

CBS CARES: Your parents seem to have had a very strong influence on you? Can you elaborate on that?

DR. HO: Well, while my parents were not very strict, they had a big influence and instilled certain important values in me. Most importantly, I've walked away from my early days with the idea that doing scholarly things and making personal sacrifices were very important. I think it has to do with my upbringing by my parents and close relatives. And so my pursuit of science is in that context. They just gave me a great deal of freedom. And, as I get older, I appreciate more and more what they have done for me. I sort of understood it intellectually when I was younger, but now I actually feel that even more strongly because my own children are growing up.

My father left Taiwan in 1957 to pursue a graduate degree in this country so that he could have a brighter future for his family. He left behind my mother (his wife) and two young kids--my brother and myself. We did not see him until 1965, about eight years. I've gone to China 24 times in the last three years, but my father did not return for eight years. I just think of the enormous personal sacrifices he made for all of us--pursuing a graduate degree in the U.S., working on the side and sending $50 back a month, which was more than enough in Taiwan in those days.

CBS CARES: How did you find out about the AIDS crisis and why have you devoted your life to the fight against this and other infectious diseases?

DR. HO: A lot of it was being at the right place at the right time. In the early '70s, I was studying physics and about to get my degree when I realized that modern biology was interesting. So, I made a switch in my last year of college and went to medical school with the idea of pursuing research. When I was done with medical training, I was just doing an extra year as chief medical resident.

It was that year, 1981, when I was preparing for my research fellowship on viruses that we saw the initial cases of AIDS in the west side of Los Angeles. Two of the first five AIDS cases that were reported were cases that I saw as chief resident.

I became fascinated by this new disease. The new disease certainly smelled like an infectious disease to me. I went after it despite advice to the contrary by some colleagues that said, "Why would you want go after something that is esoteric?" But it was right, in retrospect, having the conviction that what I was looking at was a new and scientifically important disease…something that was acquired, something that destroyed the immune system, and might be transmitted by sex.

CBS CARES: Is there anything else you want to add?

DR. HO: No, we covered a great deal.

CBS CARES: Well, thank you very much for doing this interview and giving us all this time.

DR. HO: You're welcome.