Published in the Bulletin of Experimental Treatments for AIDS Summer 1999 issue, by the San Francisco AIDS Foundation.

Related BETA Article:
Profile: Jay A. Levy, MD, AIDS Researcher

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Jay A. Levy, MD: HIV/AIDS Research at the Millennium

By Leslie Hanna

Nearly 20 years after he emerged as a preeminent HIV researcher, Jay A. Levy, MD, took some time to speak with BETA and to reflect on the current state of HIV/AIDS research and his experiences. The following article presents a world-renowned researcher's more philosophical, overarching perspectives on the HIV/AIDS epidemic. (See the sidebar for a biographical profile of Dr. Levy.)

On Long-Term Survival

I have been following a group of people with HIV infection who are long-term survivors (LTS), for 17 years. Data from some of them actually are available back to 1978, over 20 years ago, because these participants had had blood samples drawn and stored as members of the San Francisco City Cohort.

For over ten years, these people have maintained normal CD4 cell counts and an asymptomatic clinical status without having taken any therapy. Some people continue to have no detectable virus in plasma with even the most sensitive techniques. However, some are showing a trend toward declining CD4 cell numbers and toward detectable virus in the bloodstream. Still, most have not gone on therapy.

Perhaps the most striking characteristic shared by the LTS that distinguishes them from people with HIV who have progressed is the type of activity displayed by their CD8 cells. (CD8 cells are a subset of lymphocytes that are involved in controlling the spread of infections and killing antigens, or foreign invaders or cancer cells.) Essentially, CD8 cells in LTS seem to maintain a good antiviral response over time, suppressing virus replication in CD4+ lymphocytes and macrophages. The numbers of CD8 cells can be similar between LTS and people with progressive or advanced disease, but it is the antiviral activity of these lymphocytes that is most important.

This group of people, the LTS, has no lifestyle differences that I can detect that would set them apart from other people with HIV. The only thing that has come up as a theme is "survivor's guilt." Some people have expressed a desire for a support group that gathers around this theme.

CD8 Cell Antiviral Factor (CAF) Update

We know that, at least in part, the antiviral activity displayed by CD8 cells in LTS is associated with the production of a particular antiviral factor, which we have called the CD8 cell antiviral factor, or CAF. Since we first reported on this factor about ten years ago, most of our time has been spent ruling out more than 30 factors already identified and known to be produced by CD8 cells. This includes familiar cellular factors such as the interleukins, chemokines, and growth factors.

The problem with isolating CAF is that it is secreted by CD8 cells at very low levels. Its activity is therefore extremely potent. The resulting level of CAF production, however, makes it very difficult to identify. In the lab, for instance, we will need 20-40 liters of materials for identification of CAF. This objective is difficult because of the protein chemistry and cell behavior involved and also the cost. Eventually, we need to obtain the sequence and know the structure of this factor.

When CAF is finally isolated, it would be a viable candidate for a promising new anti-HIV treatment primarily because it would be natural. It might be synthesized and given as a conventional type of medication. Or, we might figure out how to stimulate CD8 cells to produce CAF, even in people with advanced HIV disease. How to go from the lab to the clinic is challenging.

Thus, the two lines of possible development would be 1) to use the factor itself or 2) to stimulate CD8 cells in the body to produce the factor. In this way, the human body itself will serve as the source of a powerful, natural immune response. Another use of CAF would be to make antibodies to it, and then to develop a test to measure the presence of CAF in the blood and in CD8 cells.

Thus far, pharmaceutical companies are not interested in helping to isolate CAF. They find the process too difficult and too time-consuming. Some companies have expressed interest in developing and marketing CAF after it's isolated, but in terms of how companies could be most helpful, involvement on the front end would be the most useful.

On When to Initiate Treatment for HIV Disease

Ed. Note: Last September, Dr. Levy published in the Lancet an essay entitled "Caution: should we be treating HIV infection early?" that generated much discussion. In this widely read essay, Dr. Levy took an unconventional stance and advocated against the prevailing standard, which was-and in many circles continues to be-to treat HIV infection as early as possible with powerful, multidrug regimens. Instead, Dr. Levy recommended caution, outlining his reasons and ideas.

Developments in the world of HIV/AIDS-research findings, insights, and feedback-since I published the position paper in the Lancet last summer have been very gratifying. More and more physicians have come around and said that they agree-that since the drugs currently available and in use can be toxic, and since they will need to be taken by individuals for a long, long time, we should wait to start therapy.

So, while the debate about when exactly to start therapy continues, more and more people are beginning to appreciate the need to reassess this issue and to use caution. In that article, I proposed not beginning therapy until the viral load has reached 30,000 copies/mL and CD4 cells are fewer than 400 cells/mm3 on two separate occasions. Some researchers in Europe are talking about starting even later, when CD4 cells are below 350 cells/mm3.

Furthermore, we have observed something of concern in people who have been on therapy for more than two years, even those who are successful in terms of high CD4 cell count and low viral burden. When we isolate their lymphocytes and look at them in the laboratory, we can see what's really happening with the immune system, as gauged by cellular activity and immune responses. Essentially we have found that in many people the immune system is not actively working against HIV. For instance, when our colleague Mike Busch and his coworkers look at ELISA [enzyme-linked immunosorbent assay, to test for antibodies made by the immune system] results, they see in people who have been on therapy for a long time that antibodies to HIV decrease. From cell studies, we have learned that even people "succeeding" on antiretroviral therapy display a decline in the function of CD8 cell responses against HIV. Now, these are people with undetectable virus-even so, upon closer inspection, we find that their immune responses are clearly impaired. It appears that the antiretroviral therapy is responsible for quieting the immune system's activity against HIV, and our goal should be to keep the immune system active.

Eventually, the debate about when to initiate therapy may be resolved by clinical trials. But the point is that, if a person is clinically healthy, rushing into therapy sheerly because of numbers-e.g., a CD4 cell count that drops below 500 cells/mm3-is a mistake: Be careful about starting antiretroviral therapy because it is a long-term commitment.

On How Best to Treat HIV Disease

People who begin taking antiretroviral therapy when they have 10,000 copies/mL of HIV RNA may rebound to 1,000,000 copies/mL when they stop therapy. It is therefore obvious that, after long-term treatment, the immune system's anti-HIV activity and responses stop, even in people apparently doing well on present medications. At the same time, while antiretroviral drugs quiet the immune response to HIV, they enable the immune system's action against other pathogens, and eventually new immune cells are brought into circulation.

Because of these observations, we are taking this approach: in addition to the accomplishments of antiviral therapy, we would like to stimulate the immune system by giving some sort of vaccine, like the Salk vaccine (Remune) or IL-2 [interleukin 2, an immune modulator]. We're now just at the beginning of this approach, but we have established a direction for future studies: restoring and increasing the immune system's response to HIV.

You see, those of us trained in virology know that, even with all of these powerful anti-HIV drugs, the virus remains ever present in cells. Antiretroviral drugs cannot take care of these infected cells; the drugs block fresh infections by free virus but these regimens cannot get rid of enough of the infected cells to ever be a "cure." There's a paper in the May [1999] issue of Nature Medicine that reports findings that suggest that it could take 60 years to get rid of all virus in T-lymphocytes. And viral reservoirs in the heart, kidneys, testes, brain, and other organs can remain, like smoldering embers; even if the fire quiets way down (i.e., circulating cells and free virus), there's always the possibility that an ember may spark a "raging fire," and the virus will spread again.

Therefore, we have some terrific anti-HIV drugs, but they need to be used at the appropriate time. I stand by what I said in the Lancet article, and I am grateful that more and more physicians are agreeing with me.

To recap, people with HIV must be careful about when to start antiretroviral therapy because we now have good evidence showing that reducing virus in the blood cells leads to decreased immune responses [to the virus]. This is why the approach from basic research labs is to ask if we can modify or motivate the immune system to recognize the virus again and regain control of it.

On "the Berlin Patient"

Ed. Note: There have been recent and rare reports (total of fewer than ten people) indicating a lack of HIV viral load rebound after starting, stopping, restarting, and restopping anti-HIV therapy for people with early HIV infection (like the now famous "Berlin patient").

These observations have led to new questions about starting and stopping therapy, or pulsed therapy. My opinion is that, under the right protocol and with very careful supervision, the sort of autoimmunization that is at the heart of this approach may work. The only danger is in creating resistance within the virus. I'd be cautious about starting and stopping too often. At present it is too early to comment on the possible widespread clinical utility of this approach.

On Vaccines

A safe and effective anti-HIV vaccine must induce a strong cell-mediated immune response. I'm not so concerned about antibodies. Moreover, this cellular response must be induced at mucosal sites.

Peter Piot, MD, from UNAIDS recently stated his belief that such a vaccine is at least ten years away (i.e., 2009). I agree! I said 15 years, 15 years ago. Since then, we have learned a lot about HIV vaccine development, particularly about what will not work.

Still, I continue to retain the hope that one of these days we'll see a big surprise in vaccine development-maybe VaxGen. Maybe it won't take 15 more years. My feeling is that we need to really emphasize vaccine research in the HIV arena, since HIV is a new kind of agent (because it hides in cells) against which a vaccine needs to be directed. This vaccine needs to deal not so much with virus entering the body, but rather with infected cells in, say, seminal or vaginal fluids. We also need to rid virus in the body as well as in genital fluids where it is a source of transmission.

I've often said HIV is like cancer. The two march together. Both diseases involve immune system responses and a cell that must be eliminated or controlled. There are many similarities between virus-infected cells and malignant cells. If we found a vaccine to handle cancer, the approach would certainly have the potential to control HIV-and vice versa.

Conclusion

At this point, nearly 20 years into the AIDS epidemic and at the end of the 20th century, the most interesting and promising arena of HIV/AIDS research is one and the same: immunology. The most exciting progress in HIV/AIDS relates to what we have been learning and continue to learn about the immune system, as well as HIV.

In immunology, we're more or less in the third grade-we've been doing really well so far; we just need to keep going, to keep learning.

Leslie Hanna is Editor of BETA.

Levy, J.A. Caution: should we be treating HIV infection early? The Lancet 352: 982-983. September 19, 1998.

Levy, J.A. HIV and the pathogenesis of AIDS. 2d ed. Washington, DC: American Society of Microbiology. 1998.

Levy, J.A. HIV pathogenesis and long-term survival. AIDS 7: 1401-1410. 1993.

Levy, J.A. Surrogate markers in AIDS research. Is there truth in numbers? Journal of the American Medical Association 276: 161-162. 1996.

Siciliano, R. and others. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Medicine 5(5): 515-519. May 1999.

Page last updated 5 October 1999