Research Initiative Treatment Action (RITA!); Vol 5, No. 4 October 1999
Paul Simmons, RN, ACRN
This much is known. HIV infection almost invariably produces a relentless, if sometimes slow, decline in CD4 T cell count. That decline and other immune system abnormalities leave people with HIV vulnerable to opportunistic pathogens and tumors, which eventually cause death.
But what is it, exactly, about HIV's presence in the body that brings about CD4 T cell decline? Does the virus destroy these cells? Does it inhibit their production? Does it do both? Are the cells committing suicide? Could it be, as some researchers have suggested, that HIV actually protects infected CD4 T cells—at least until the cells produce more virus?
The answers are unknown, but the questions are the subject of intense scientific inquiry and controversy.
Early on in the epidemic, most scientists thought that HIV caused a latent infection. Once a person acquired the virus, it lay quietly in the body and became active only after several years. Then in 1996, David Ho, MD, published work showing that HIV was always active, replicating daily at high levels. Some of Ho's work has since come under fire, but his core tenet—that HIV is a constantly replicating virus—is now accepted theory.
Researchers have long known that HIV preferentially infects activated CD4 T lymphocytes, cells that play a crucial role during an effective immune response. But not all CD4 T cells respond to every infection. For example, CD4 T cells responsible for containing a virus that causes the flu will not react to a virus that causes hepatitis. Each subset of CD4 T cells is therefore directed against a particular antigen.
Based on this understanding of how CD4 T cells work, many researchers have suggested that CD4 T cells specific to HIV are lost early in the course of infection. After all, if HIV preferentially infects activated CD4 T cells, the activated CD4 T cells directed against HIV itself would be particularly vulnerable to infection.
Bruce Walker, MD, of Harvard has relied upon this understanding of pathogenesis to support his view that people infected with HIV should receive treatment early in the course of infection—during or before acute retroviral syndrome. Up to 70% of HIV-infected people suffer the flu-like symptoms of this syndrome, which occurs two to 4 weeks after infection.
Walker believes that by suppressing HIV in the first weeks of infection, HIV-specific CD4 T cells, which would otherwise be lost, are preserved. If rescuing these cells enhances the immune response to the virus, it may be possible to one day discontinue antiviral drugs.
Unfortunately, many, perhaps even most who experience acute retroviral syndrome either do not seek medical attention or, if they do, their illness is often misdiagnosed as the flu. In any event, the overwhelming majority of people with HIV are in the chronic phase of the infection, well beyond acute retroviral syndrome. So when the Walker hypothesis first became widely known in 1998, it was not encouraging for most HIV-infected people. But theories about the pathogenesis of HIV are a lot like Texas weather. If you do not like them, wait a moment. They will change.
In May of this year, Louis Picker, MD, and his colleagues published a paper at odds with the Walker hypothesis. HIV-specific CD4 T cells, Picker's group reported, are present at "significant frequencies" in most people with active, chronic HIV infection. This finding, if true, may have important implications for understanding HIV pathogenesis. For one thing, it suggests that HIV is either only weakly cytopathic, or that the immune system possesses mechanisms capable of counteracting antigen-specific cellular destruction.
Whatever the case, the clinical implications of Picker's finding are not immediately clear. He writes, "Our data indicate that ... HIV specific CD4 T cell help is available in most subjects during clinically 'silent' years of HIV infection." And yet he also finds that the frequency of these cells is not correlated with viral load. In other words, someone with a higher viral load may have as many, if not more, of these cells as someone with a lower viral load. This raises a question. If the presence of these cells is not related to viral load suppression, what good are they?
Perhaps the significance of Picker's discovery is not the discovery itself, but what it may suggest about either HIV pathophysiology or the workings of the immune system or both. Picker's findings are consistent with those of other scientists, including Marc Hellerstein, MD.
In January, Marc Hellerstein, MD, and his colleagues published a Nature Medicine paper showing that HIV's principal effect is the inhibition of cellular production. In commenting on the paper, Giuseppe Pantaleo, MD, wrote that while there may be CD4 T cell destruction, it is not as much " ... as previously estimated and by no means enough to explain overall CD4 T cell depletion." Picker's findings are consistent with Hellerstein's work. But Picker elaborates on the ways in which the immune system compensates for CD4 T cell loss. As the number of CD4 T cells diminishes over the course of infection, Picker postulates that the immune system through homeostatic mechanisms preserves its response to the antigens most frequently presented. Since HIV is a chronic infection, Picker asserts, the immune response maintains its response to HIV antigens.
If that is true, the collapse of the immune system's response to HIV should reflect the apogee of a long march to immune decline—and it does. In late stage disease, by the time the immune system is contributing little, if anything, to the control of HIV, it has generally lost its ability to control any other pathogen as well.
While these latest investigations into HIV pathogenesis suggest that the virus is inhibiting the production of immune system cells, so far no one has identified the means by which the virus does this. Discovery of the mechanism by which HIV inhibits cell production would allow for new therapeutic approaches.
Ironically, these new insights bring science full circle to Ho's theory, major portions of which now lay in tatters. Ho postulated a massive immunologic war with billions of virions produced daily—true—and billions of T cells produced daily—not true. Ho postulated that eventually the immune system becomes exhausted, unable to produce enough cells to replace those destroyed by HIV. So even if it is disruption of homeostatic mechanisms and inhibition of production&mdah;rather than exhaustion of production—that lies at the heart of HIV pathogenesis, Ho was not far from the truth: HIV wears out the immune system.
Significant rates of clinical drug failure—to say nothing of toxicity—suggest that antiviral "cocktails" may not be the best way for the body to rest. Fortunately, as the dawn of a new millennium breaks, investigators are turning their attention to the immune system and therapies that boost it.
Not a moment too soon.
Antigen: a foreign substance, usually a protein that stimulates an immune response.
Pathogenesis: the origin and development of a disease.
Cytopathic: producing pathological changes in cells, including cell death.
Pathophysiology: the study of how normal physiological processes are altered by disease.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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