Research Initiative Treatment Action (RITA!); Vol 5, No. 1 January 1999
Paul Simmons, RN, ACRN
What is AIDS?
"Is it mainly a disease of cell production or destruction?" asks Marc Hellerstein, MD of San Francisco General Hospital.
Hellerstein may have answered his own question in a recently published ground-breaking paper. The paper, entitled "Directly Measured Kinetics of Circulating T Lymphocytes in Normal and HIV-1-Infected Humans" (Nature Medicine, 5:1, 83-89), challenges the widely held understanding of how HIV causes disease. Since 1995, most scientists have believed that HIV exhausts the immune system by killing the CD4 T cell. The CD4 T cell orchestrates the body's immune response as is considered to be the general of the body's disease-fighting army. Hellerstein does not deny that HIV is cytopathic; instead, he provides evidence that the virus is primarily shortening the survival time and inhibiting the production of CD4 cells.
According to Joseph McCune, MD, a researcher at the University of California and a co-author of the paper, "This study tells us HIV does two things. It does destroy cells, but its main effect appears to be on the systems of cell production. What that tells us is that we have to get rid of the virus, no question about that. But we really need to focus our attention on the systems of cell production." ("Study Offers new Theory of How HIV Attacks Cells, San Francisco Chronicle, January 5, 1999.)
Hellerstein examined the kinetics of CD4 and CD8 T cells in HIV negative subjects, in HIV-infected subjects not on treatment and in HIV-infected subjects taking highly active antiretroviral therapy (HAART).
The healthy subjects had CD4 and CD8 T cells with half-lives of 87 days and 77 days, respectively, and they produced CD4 T cells at a rate of 10 per microliter per day and CD8 cells at a rate of 6 per microliter per day. (See appended information at end of this article.) For patients whose HIV infection had not yet been treated, the half-lives of the CD4 and CD8 T cells were less than a third of what they were for the healthy volunteers; moreover, the infected subjects were not compensating for this decrease in cell survival time with increased cell production. This shortened survival time in the absence of increased production could explain the CD4 T cell loss leading to AIDS.
In 1995, David Ho, MD, turned the world's understanding of HIV upside down by arguing that HIV kills billions of CD4 T cells daily and that the immune system compensates by producing billions of cells daily. Until then, most physicians and researchers had assumed that HIV was latent, or quiet, for several years and became active—for unknown reasons—only late in the course of disease. Ho's hypothesis squarely contradicted the wisdom of the day. And Hellerstein's paper squarely contradicts Ho's hypothesis.
Hellerstein and his colleagues do not dispute that HIV is directly killing some CD4 T cells. (Indeed, shortened cell survival time is consistent with virally mediated cell destruction.) Nor do they deny that the immune system itself is also destroying virally infected cells. But as Giuseppe Pantaleo, MD, says in an editorial accompanying the Nature Medicine article, there is not as much T cell destruction "... as previously estimated and by no means enough to explain overall CD4 T cell depletion." "If there is destruction," Pantaleo writes, "in the absence of increased production, lost T cells will not be replaced, suggesting that limited renewal/production of CD4 T cells could be a primary mechanism for the progressive depletion of CD4 T cells in HIV-infected subjects." ("Unraveling the Strands of HIV's Web," Nature Medicine, 5:1, 27-28.)
Hellerstein's theory—the third in the history of the epidemic on how HIV causes CD4 cell loss—does not have any immediate clinical implications. It is, however, rich in implications for research. Current therapy for HIV is aimed at shutting off the virus. If Hellerstein and his colleagues are right, a new approach to treatment is needed—one aimed at protecting or enhancing CD4 T cell production.
This latest theory of pathogenesis does not answer the questions of exactly where or how HIV damages CD4 T cell production. The three most likely explanations are that the virus: 1) prevents CD4 progenitor cells from emerging from the bone marrow, 2) inhibits CD4 precursor cells from maturing in the thymus, or 3) impairs the life cycle of CD4 T cells or their ability to send and receive chemical messages.
CD4 T cells are lymphocytes and all lymphocytes originate in the bone marrow. HIV may inhibit bone marrow production of the T-cells' progenitor, or parent cells. Some lymphocytes—those destined to become T cells—migrate to the thymus, and it is possible that HIV is blocking the maturation of CD4 precursor cells in the thymus. Finally, HIV might disrupt what scientists call "cell signaling," or communication between mature cells.
Hellerstein's paper is sure to generate debate among researchers. Anthony Fauci, MD, director of infectious diseases at the National Institutes of Health, told the San Francisco Chronicle, "This is a controversial area. I think it will remain a controversial area. It's a good paper ... but the jury is still out." The paper also reports some counterintuitive findings—ones for which Hellerstein and his colleagues offer no cogent answer. For example, Hellerstein reports that in HIV-infected volunteers who received HAART, T cell production increased while cell survival time decreased even further. Why? The authors reply with a hand wave. The shorter half-life, they say, "... may reflect complex underlying population dynamics."
Still, by providing fresh insights into an old question—What causes the CD4 cell loss that leads to AIDS?—Hellerstein points the way to new and better research. "The answer," he says, "can totally change your biological focus."
1Production rate of CD4 lymphocytes, per microliter, per day.
"The thesis of our paper is that HIV affects the system of production more than it induces destruction of mature T cells," says McCune ("T Cell Production: Slowed, Not Exhausted?" Science, 283,5400: 305-306). But look at the baseline CD4 counts for the three groups. Patients with HIV had much lower numbers and yet their rates of CD4 production were statistically equivalent to the HIV negative controls. According to Ho, the same production rate between a group with high CD4 counts and one with low CD4 counts must mean the T cell turnover is greater in the lower count group (Ibid).
Notice also that CD4 survival time drops even further among the HAART-treated, HIV-infected volunteers. Why?
Cytopathic: producing pathological changes in cells, including cell death.
Kinetics: mechanism by which physical or chemical changes are affected.
Half-life: the time required for half the amount of something to be eliminated.
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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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