The HIV “Elites:” Viral Controllers and Their Genes           

By Jeffrey Laurence, M.D.

amfAR grantee Dr. Steven Deeks

December 13, 2010 - For more than a decade, Dr. Steven Deeks of the University of California, San Francisco, has been trying to solve an important puzzle. How are a small number of HIV-infected individuals who are not taking antiretroviral therapy (ART) able to maintain low viral loads and near normal CD4 T-cell counts? The answer to this critical question may provide a clue in the design of an effective AIDS vaccine, a goal that has eluded researchers for decades. With support from amfAR, Dr. Deeks and his colleagues at UCSF have assembled a large cohort of these individuals, known as “elite controllers,” and is collaborating with other groups to determine how the immune system keeps their virus in check.

In a recent study led by Drs. April Ferre and Barbara Shacklett at the University of California, Davis, Deeks and his colleagues  obtained blood samples and biopsies of rectal tissue from 52 HIV-positive patients: 28 elite controllers, 14 “noncontrollers” who were not on treatment, and 10 noncontrollers on ART who maintained undetectable viral loads. The biopsies were necessary as the intestinal tract is a key site for HIV transmission, growth, and depletion of T cells, and has often been overlooked in studies of elite controllers.

The researchers found that many study participants, both controllers and noncontrollers, had similar levels of HIV-specific CD4 T cells—immune cells that direct the response of the immune system to the virus. But the controllers had “unusually strong” CD4 T cells in their rectal tissue, cells capable of recognizing proteins known as Gag proteins, which form the core of the virus. In some controllers, more than one CD4 T cell in every 10 counted proved to be HIV-specific. This level was much greater than what was found in participants who required ART to keep circulating levels of virus low. Controllers also had higher levels of multi-functional CD4 cells in rectal tissue than noncontrollers or those on ART. Along with these super-functional CD4 T cells, another type of immune cell known as the CD8 T cell was also present at much higher levels in controllers. This finding makes sense, since CD8 T cells are under the control of the CD4 T cells that are especially virulent in controllers.

In exploring possible genetic explanations for viral control, the researchers found that controllers with the strongest HIV-specific CD4 cells had at least one of two genes associated with defining tissue type: DRB1*13 and DQB1*6. These genes have previously been linked to HIV-positive individuals called nonprogressors, who do not progress to AIDS despite lack of treatment. Deeks and his colleagues have broadened our understanding of this phenomenon with their finding that those lucky enough to possess both DRB1*13 and DQB1*6 have T cells with super-strength in recognizing HIV.

The team concluded that the preservation and expansion of both HIV-specific CD4 and CD8 T cells may be key mechanisms by which HIV controllers keep their virus in check. Their findings suggest that HIV vaccines and therapies aimed at enhancing these intestines-associated T-cell responses should be actively pursued.

Dr. Laurence is amfAR’s senior scientific consultant.

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