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.