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Early Treatment Cuts Infection of Resting CD4 Cells

, by San Francisco AIDS Foundation

During the “acute” phase of HIV infection—the first weeks after exposure—the virus hijacks the genetic material of important immune system cells, called CD4 T-cells, and uses them to replicate (make more copies of itself).

HIV also establishes “viral reservoirs” in CD4 cells that are in a resting state—that is, they are not “on duty” in the immune system, and are essentially invisible to other immune system cells, called CD8 “killer” T-cells, whose job is to snuff out infected cells. These HIV-harboring resting CD4 cells are referred to as “latently infected.”

Because the HIV in these reservoirs is not actively replicating, it is not susceptible to antiretroviral drugs, which work by interrupting various stages in HIV’s lifecycle. Any attempt to cure HIV by eradicating the virus from the body must address the problem of viral reservoirs.

That might be an easier task if fewer CD4 cells were latently infected to begin with. In this article from HIVandHepatitis.com, Liz Highleyman explains new research on latently infected CD4 cells that has implications for treating—and curing—HIV.

[BETA editor’s note: The research discussed here suggests yet another benefit of starting treatment early in HIV disease—although the catch is that most people in acute HIV infection don’t yet know they are infected.

During this “window period,” the immune system has not yet begun to produce antibodies to help fight the virus. This can lead to unreliable results from regular HIV tests, which look not for the virus itself but for the antibodies to it. Another type of test, called an RNA test, looks for HIV’s genetic material and can give more reliable results during acute infection but is not generally used for routine HIV testing. Click here for a description of the two tests and some HIV testing basics.]

 

Immediate Antiretroviral Therapy Reduces HIV Infection of Resting CD4 T-Cells

By Liz Highleyman, Editor in Chief, HIVandHepatitis.com

Starting antiretroviral therapy (ART) during the acute phase of HIV infection appears to reduce the number of latently infected resting CD4 T-cells in most people, but this may not be the case for individuals with very few initially infected cells, according to a study published in the May 29, 2012, advance online edition of Proceedings of the National Academy of Sciences.

One of the reasons HIV is so difficult to eradicate is that it can insert its genetic material into resting T-cells. As long as these cells remain quiescent, this persistent virus is “silenced.” This reservoir of latent HIV is not vulnerable to antiretroviral drugs, which only work when the virus is replicating. If the cells become activated, however, the viral DNA they contain can begin producing new infectious virus particles. A better understanding of viral latency can provide clues to help develop a cure.

Nancie Archin and David Margolis from the University of North Carolina at Chapel Hill and colleaguesexplored the viral kinetics of resting cell infection using a mathematical model that predicts the initial frequency of infected resting cells measured about 1 year after infection, based on the time of ART initiation and dynamic changes in HIV viral load and CD4 cell count.

Results

  • The model indicated that in a majority patients who start treatment during acute HIV infection—while still seronegative—early ART would reduce the generation of latently infected cells.
  • In this group, resting cell infection usually declines after the first year on ART.
  • When resting cell infection had a frequency of less than 0.5 per million, however, the model showed a “striking absence” of decline in infected cell numbers.
  • Here, low-level viremia was observed more frequently as resting cell infection increased.

These findings, the study authors wrote, “suggest that…the degree of resting cell infection is directly related to the availability of CD4+ T-cells susceptible to HIV, regardless of whether virus levels are controlled by the immune response or antiretroviral drugs.”

They also surmised that “2 pools of infected resting CD4+ T-cells exist, namely, less stable cells, observable in patients in whom viremia is not well controlled in early infection, and extremely stable cells that are established despite early ART.”

These results, they concluded, “reinforce and extend the concept that new approaches will be needed to eradicate HIV infection, and, in particular, highlight the need to target the extremely small but universal, long-lived latent reservoir.”

6/12/12

Reference

NM Archin, NK Vaidya, JD Kuruc, et al. Immediateantiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proceedings of the National Academy of Sciences USA. May 29, 2012 (Epub ahead of print).

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