The hope whisperer.

As the top researchers met in Geneva Earlier this month, an AIDS-weary world Again turned to David Ho for answers

Two years after proposing HIV could be eradicated from the body, David Ho faces many obstacles. Still, he remains optimistic

In 1990 David Ho became the chief executive officer and first employee of the Aaron Diamond AIDS Research Center in New York City. Today, he oversees a staff of 100. In the interim the center has changed the way researchers and the public think about HIV. Ho and his colleagues have shown that contrary to prevailing wisdom, the virus begins to replicate itself massively immediately upon infection. They have been among pioneers of therapy. And most dramatically, as discussed at the 1996 International AIDS Conference in Vancouver, Canada, Ho has posed the theoretical possibility that HIV can be eradicated from the body. As a of the advances made in AIDS treatment that year, Ho was named Time magazine's Man of the Year. The honor was the culmination of more than 15 years on the front line of the AIDS war. As chief medical resident at Cedars-Sinai Medical Center in Los Angeles in 1981, Ho was among first doctors to witness the strange, then-unnamed syndrome that was claiming the lives of gay men and quickly suspected that a virus was the cause.

In an interview in his office prior to his departure for the World AIDS Conference in Geneva, Ho talked to The Advocate about a wide range of topics, including the obstacles to eradication and a vaccine, the rise in unsafe sex among gay men and the continuing impact of his Man of the Year honor.

What do you think the major topics and issues are going to be at the upcoming World AIDS Conference in Geneva?

Well, I'm not expecting major surprises. I expect people to continue to talk about incremental developments in the field. In therapy, for example, I think people will be talking about one regimen versus another and talking about some of the problems that we're facing. People will continue to update us on the declining mortality in the United States and Western Europe. I think the trend will continue even though we all recognize that there are going to be failures that will continue to pop up.

A very different tone from Vancouver then?

To me, Vancouver was just another increment. Some of the developments were blown out of proportion, even some of our work that was featured in that process. We went and gave a very concise, limited talk on some of the theories behind eradication. In some people's minds that got translated into "eradication." That's not appropriate.

What are you going to be talking about in Geneva?

I'm going to talk about the obstacles to viral eradication; that is, the latent pool [of virus] that remains after several years of treatment. We are trying to understand that pool, how big it is, how quickly it's decaying or how slowly it's decaying, whether that pool contains virus that might be different from the other virus [and] to talk about some of the strategies to contend with the remaining virus, how we might be able to induce its activation and therefore its elimination. I'm going to talk about how we could perhaps somehow boost the immune responses in these individuals so that we could perhaps ask the immune responses to substitute for the drugs.

Are you sorry you ever used the word eradication?

I think the first mention of the word came from a meeting titled "HIV Eradication?" in which I did not participate, some weeks preceding the Vancouver meeting. We obviously had been thinking along that line, but we had never dared to use that word. It's interesting that in our field we've been so shy about it until the past couple years. In cancer a cancer cure has been talked about for a long time, and it's OK as an objective. It's taboo in AIDS.

I've heard that you recently suggested that it might be possible to talk about eradicating the virus from the body in 20 years.

It might be possible in 20 years. I think those are the kinds of questions we're trying to answer. I don't think anyone has enough data in hand to be absolute about any of these issues. I know many groups are working to define these parameters so that we could make a logical prediction about how long it would take for this residual pool to disappear and whether there are other obstacles in the way.

Such as?

Such as the fact that virus might be in the brain. If it's hiding out in a protective sanctuary, how do you deal with that? That's another issue that could affect these estimates. And I think whether I tell you it's going to be five years or seven years or 20 years, these are all estimates. One comes to the conclusion that based on the information available today, it's going to be a long period of treatment before this residual pool of virus will go away.

One thing I've read about is somehow tricking the virus to come out of hiding.

The virus is dormant in these cells that are in a resting state. So the cell would not attempt to make any virus until it's stimulated. So one strategy--this is theory now--would be to turn on the T-cells. If a sufficient number were turned on, you could make a substantial move in shrinking the population that remains. One strategy would be to give something that would activate resting T-cells. This is not a trivial matter on a practical level. And we also have to be careful about turning on lymphocytes too much, because in fact we know that, from many other illnesses where generalized activation of the lymphocyte population is a severe syndrome.

And other places, like brain tissue, where the virus might be hiding?

The brain is something that is also, in theory, addressable. The approach would be to come up with drugs that would penetrate into the central nervous system. The problematic ones are the currently available protease inhibitors. As more drugs come along, those would be ones to entertain because they would fit in rather well.

The assumption is that combination therapy works indefinitely. When I talk to people with HIV, they keep waiting to hear the other shoe drop.

It's impossible to answer [the question of how long combination therapy works] with any degree of certainty right now. We have a lot of patients in whom the virus has been suppressed between two and three years. Whether this would hold up two more years down the line, five more years down the line, would depend upon empirical observation. We simply have not had sufficient experience with these patients at this point.

There's also the sense that if the current batch of drugs doesn't hold out, there will be something else in the pipeline.

It depends on who the patient is. If somebody has been through a lot of the drugs already and they have responded to a new combination but have very few options left, it could be problematic. But if you're a patient who is on the first combination, with perhaps backup combinations available, the scenario doesn't look so bad.

The second half of this equation is stopping the virus in its tracks with a vaccine before it gets anywhere. Can you tell me a bit about your own research in that area?

I think all of us at this institute feel that advances in drug therapy are great for American and European patients, but it's really not helping the epidemic on a global level. Therefore, we would like to contribute to vaccine development because, I think, prevention is the key to the whole epidemic. We'd like to focus on DNA vaccine strategies, live-vector vaccine strategies, and also efforts to modify the HIV envelope to see if that somehow could result in an immunogen that would be better at stimulating antibodies to the virus. We're taking a multipronged approach simply because we don't think there's a clear blueprint for building an effective vaccine. The only one from animal experiments is the live-attenuated vaccine strategy, and we don't think that's sufficiently safe for us to pursue that further for human investigation.

What constitutes a successful vaccine?

We have been shooting for the moon for a long time, asking that a vaccine protect against virus infection--period. If you look back on the available data from many, many other viral vaccines, many of them produced enough immunity to suppress the infection, so it caused no disease. That's the first question we have to ask. Are we trying to protect against infection, which is the ideal situation, or could we let infection take place but with enough immune responses present to somehow suppress the virus so that there is no disease?

Do you find it frustrating to read accounts of increased risk in people's behavior?

Yes. I think that's a reflection of complacency setting in. There's been a great deal of success in reducing transmission, particularly among the young gay population. But some of the things I've heard out of certain urban areas, such as San Francisco and New York, bother me. There is good news, but that good news isn't a cure. We know that good news is associated with complications and toxicity. This is not like catching gonorrhea, where you can take specific antibiotics for it and in a few weeks' time get rid of it. We're seeing decreases in new infection in developing countries, in such places as Nairobi [Kenya] and Bangkok [Thailand]. But to see the resurgence of reckless behavior in the U.S. is certainly disappointing, and it suggests that prevention efforts have to be continuous.

What's it like to be named Time's Man of the Year?

It's a mixed blessing. There are wonderful benefits that occur occasionally. But with that honor comes responsibility. I'm put in the position to help educate the public and, to some extent, the leadership about the problem. I've gotten more invitations to speak to college groups and, to some extent, high school groups, and I tend to take that responsibility quite seriously. It occasionally gives me access to "important" people, and I use those opportunities to tell them about this particular problem so that it doesn't disappear from their consciousness. But if I do those things, I can't spend the time doing the research. I know that this honor in many ways is meant for the whole field. They had to pick someone to represent the field, and I was the chosen one. I used to tell people I was the poster boy for AIDS research. That is fine; I've learned to live with it. But that sort of recognition comes with a lot of jealousy also, which can be excessive at times.

Clearly you've seen a lot of patients and colleagues die from the disease. What are your personal reflections on the epidemic?

I indeed have lost a lot of patients, and some of those patients I would consider dear friends. There have been colleagues lost along the way. It's been difficult. But I've never suffered the typical burnout. My enthusiasm is as high as ever. It's fueled not only by the recent success. I think it's really fueled by the fact that we've learned so much. There's also a faith that ultimately this knowledge will translate into something practical we can use to fight the virus. I think the recent progress is the beginning of this process.