Research Initiative Treatment Action (RITA!); Vol 5, No. 3 July 1999
Paul Simmons, RN, ACRN

When confronted with an invading pathogen, the human immune system usually responds with precision and power, and the infection is either cleared or at least controlled. Sadly, in the presence of HIV, key elements of this response are hobbled, and the host is left susceptible to an array of opportunistic microorganisms.

HIV is itself an immunogen, and yet it manages to escape definitive immunologic restraint. The mechanisms of this escape are not fully known, but several investigators have suggested that HIV-specific CD4 memory cells are usually scant. CD4 cells act as generals of the body's disease- fighting army and are essential to an effective immune response, including a response against HIV. If CD4s specific to HIV are either meager or absent, as many believe, this may partly explain why the body fails to clear the virus.

Now, Louis Picker, MD, and his colleagues, in a paper written for Nature Medicine,¹ argue that HIV-specific CD4 memory lymphocytes persist in the face of chronic infection. Moreover, he suggests that long-term highly active antiretroviral therapy (HAART) diminishes the frequency of these cells.

CD4 lymphocytes targeted to HIV have been thought to persist only in long-term non-progressors or in acute seroconverters rescued by early therapy. But Picker reports that " ... significant frequencies of such cells are detectable in most subjects with active HIV infection."

According to Picker, CD4 memory cells responsive to HIV antigens were present, as expected, at high frequencies in long-term non-progressors. But his group also found these cells in patients with active infection, which is surprising and suggests that HIV disease progression cannot be comprehensively explained by the loss of memory lymphocytes directed against the virus.

The group further reports that these memory lymphocytes were dramatically reduced in subjects treated for a year or longer with antiviral therapy. If true, this finding may help to explain the rapid return of viremia in patients who discontinue treatment. Ironically, it might also help to explain why HIV sometimes rebounds even in the individual whose viral load is maximally suppressed by HAART. If effective, long-term treatment results in a sharp reduction of HIV-specific CD4 memory cells, the immune system may lose its ability to control escape mutants.

In an earlier paper written for Science,² Eric Rosenberg, MD, and his colleagues reported that CD4 memory cells are important for controlling HIV infection. He showed a negative correlation between the rigor of CD4 memory response to HIV antigens and viral load. But Picker disputes this. He writes that " ... HIV specific responder frequencies in subjects with active disease did not strongly correlate with plasma viral load."

Picker's ability to find HIV-specific CD4 memory lymphocytes in subjects with progressive infections suggests that these cells—while perhaps essential—are not enough to control the virus. He writes, "These observations indicate that the relative frequencies of CD4 T cells cannot by themselves completely explain the differential ability of HIV-infected subjects to intrinsically control viral replication and disease progression."

Since HIV-particular CD4 memory cells were not correlated with viral load, could it be that the presence of these cells in long-term non-progressors is effect and not cause? In other words, are long-term non-progressors the lucky few infected with an attenuated virus, thus allowing HIV-specific CD4 cells to survive in especially large numbers? Picker does not think so; he found no evidence of attenuated virus among the non-progressors in his study (personal communication).

If Picker and his group are right that individuals infected with HIV can generate virus-specific memory CD4s, pulsing antiretroviral therapy may act to boost the number and function of these cells. Repeatedly suppressing antigen and then re-presenting it to the immune system could skew the T-cell population in favor of cells responsive to HIV. This, in turn, may ultimately provide the immune system with an edge in its fight against the virus. Reports suggest this approach may have already helped to control HIV in a few cases. The so-called "Berlin patient"—who repeatedly started and stopped therapy—is probably the best known example. His viral load has been undetectable for almost two years without antiviral therapy.

The Adult AIDS Clinical Trials Group, a consortium funded by the federal government to conduct HIV research, will launch a pilot study this year to explore the concept of pulsing. Unfortunately, data from that trial will be unavailable for two to 3 years.

Even if the clinical applications of his paper are not immediate, importantly Picker's work offers a challenge to a core theme of HIV dogma. Virally mediated destruction of CD4 lymphocytes is widely accepted as explaining the loss of these cells in the natural course of HIV infection. But Picker's finding that high viral load and high frequencies of HIV-specific CD4s can co-exist suggests other possibilities. HIV-induced cytolysis may play less of a role in T cell loss than generally thought, or the immune system may possess a greater regenerative capacity than previously believed.

Whatever the case, Picker's work calls for new basic science investigation.

¹ Nature Medicine, 1999 May;5(5):518-25.

² Science, 1997 Nov 21;278(5342):1447-50.

Immunogen: a substance capable of inducing an immune response.

Acute seroconverters: individuals recently infected with HIV who are going from antibody negative to antibody positive.

Antigens: substances capable of inducing an immune response.

Viremia: presence of virus in the blood.

Escape mutants: virions that have mutated to escape control by the immune system or suppression by antiviral drugs.

Attenuated: weakened.

Pulsing: : a controlled, structured approach to treatment in which antiviral drugs are completely and abruptly withdrawn, reintroduced at a fixed interval and then completely and abruptly withdrawn again; not to be confused with non-compliance or suboptimal drug-taking.

Cytolysis: destruction or breakdown or a living cell.

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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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