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