The Next Step in AIDS Research
Dr. David Ho was the fourth scientist to identify the virus that causes AIDS, but he has rarely lagged behind other researchers since then.
In 1991, Ho and Dr. George Shaw confounded then-current theories about HIV replication by demonstrating that the virus reproduced billions of times a day, but was kept under control by an ever-weakening immune system. Scientists had previously believed that the virus lay dormant in human beings for as long as 10 years after infection before beginning such a frontal assault.
That discovery suggested that HIV should be attacked with antiviral drugs as soon as possible after infection, and Ho, director of the Aaron Diamond AIDS Research Center in New York City, was among the first to use protease inhibitors to treat such patients. He also pioneered the use of combinations of three or more drugs to treat patients--a treatment that lowered the level of the AIDS virus in the patients’ blood below detectable levels.
In light of the successes with this triple therapy and the prospect of a “cure” for AIDS, Ho was named 1996 Man of the Year by Time.
Last November, however, Ho’s group was one of two teams to report that HIV was still present in patients who had been treated with triple therapy for two years or more, hiding in white blood cells called memory T cells. Such cells have been primed to recognize a foreign object (antigen) such as a virus during an infection, and are left behind as sentinels for subsequent exposure to the antigen. They do not replicate while in this resting state and the virus cannot be killed until the cells start replicating.
The discovery that such pockets of virus remain in patients who have been treated for so long suggests that HIV-positive individuals may have to take drugs for the rest of their lives.
Ho, 45, recently met with The Times after addressing a symposium at UCLA.
THE TIMES: You’ve talked a lot about the possibility of taking some patients off triple therapy after 18 months or two years. Were you disappointed to find these reservoirs?
HO: We weren’t celebrating, but it’s actually not that much of a surprise because we knew HIV could be in those resting cells in a latent way. But I think it makes clear what we need to do. We now have to take the problem head-on and deal with it, see if we can activate the cells and get them to [replicate].
THE TIMES: Are there specific things you are going to do?
HO: Yes. We’re not doing it today, but we are exploring several strategies. We’re exploring to see if administering certain antigens might stimulate enough cells to [replicate]. We’re exploring whether cytokines [substances produced by white blood cells], particularly tumor necrosis factor, might make them [replicate]. And also, there are monoclonal antibodies, called anti-CD3 antibodies, that turn on all T cells. But obviously that has to be done very carefully, because if you get too much immunological activation, that in itself is associated with a lot of toxicity.
THE TIMES: What kind of antigens?
HO: There are some simple things we could do. Take, for example, all the things that we would give to people to vaccinate them--flu antigen, pneumococcal antigen, anything that would stimulate the immune system . . . in a very select way: one antigen, one population [of T cells]. There are also these things called super-antigens, which could stimulate nonspecifically.
THE TIMES: What might be the danger?
HO: Too much activation. And obviously, if you have too much activation, then you have a shock-like syndrome that should be avoided at all costs. So these studies are likely to be ones that escalate the dosage very carefully over time.
THE TIMES: What have been the biggest advances over the past year?
HO: I think the biggest advances continue to be in a few areas. We’re still making steady progress in therapy, even though the new studies uncovered one obstacle. There are a lot of advances being made at the basic science level--understanding how host genetic differences are actually affecting the disease; disease rates; disease progression. These things have become clearer, beginning about 18 months ago, but more so in the past year.
And the fundamental discovery a year ago of co-receptors for HIV has allowed us to develop drugs against co-receptors. Although you are not hearing about the testing of these drugs in patients this year, a year or two from now we will. Many, many inhibitors of the co-receptor have been found over the past year.
THE TIMES: When should therapy for HIV infection begin?
HO: From a theoretical viewpoint, there are a lot of reasons to say we should start early. If you start late, the immune system becomes damaged and we don’t have good ways of repairing it. In addition, the later you start, the more complex the viral population is, the larger the viral population is, and consequently the more difficult it is to control it.
In general, for most infections, you treat them as early as possible. HIV has been the sole exception for a long time, and that was because of the therapies that were available to us in the decade of the 1980s. It didn’t matter whether you treated or not. But that is no longer the case. Clinical trial data shows that early intervention gives you the best outcome. And to treat appropriately, not with one drug at a time, but with these combinations.
THE TIMES: How successful is triple therapy?
HO: We have a success rate of about 80%, taking into account that “failures” are related to not being able to continue the regimen--for reasons of toxicity, for reasons of human behavior and the difficulties involved in sticking to a complex regimen. It has been our experience that if you look at patients who are normal, if they stick to [the regimen], and if they are early patients who have never taken drugs before, there are no exceptions. Everyone can have the virus reduced to undetectable levels.
THE TIMES: A recent report from UC San Francisco said that the failure rate was more than 50%.
HO: If you go to patients who have already taken a lot of AIDS drugs, who are in a late stage of disease, yes, there are high failure rates. That report that came out of San Francisco was almost the worst-case scenario. It started in the 1995-96 period, with hospitalized patients who had taken many, many different drugs and were very sick. And what do you mean by failure? In that study, they measured viral load. So if you had any detectable viral load, even if it was very low, it was classified as a failure. But clinically, that patient was still a success. And now there is this prevailing sentiment throughout the country that these combinations result in failure in about half the patients. That’s simply not true.
THE TIMES: What can we do for those people who have already had therapy and have developed resistance to the drugs?
HO: I think the best thing we can do is bring along new drugs, unfortunately. There is a drug called PMPA. Initially, it could only be given intravenously; now it’s being brought along in an oral formulation. It’s very powerful and has different resistance patterns, so it is likely to offer something to patients. The same thing for Abbott’s new protease inhibitor, it goes by ABT378. On paper, it looks very good against HIV and probably could hit a lot of drug-resistant variants. And there are several other examples.
THE TIMES: If you had to identify one goal right now, what would it be?
HO: I think, for the short term, if we knew how to flush out this reservoir, I would be very happy. In the long term, I have already shifted over half of my research effort to vaccine development--in my own laboratory and a good part of our institute. In the long run, I think AIDS will become, in this country and Europe, a more manageable disease. And so, consequently, the real, huge problem will be in the developing countries. And the only way we know how to tackle that is through vaccines.
