A new study confirms what HIV researchers until now only suspected: HIV selectively disables the immune system's response against the virus by disproportionately infecting the very cells designed to fight it. In fact, CD4+ T cells programmed to fight HIV are two to five times more likely to be infected with HIV than CD4+T cells programmed to take on other pathogens.
"This finding not only helps us better understand how the virus causes disease, it should also aid in developing effective HIV vaccines," comments Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID). The study, conducted by scientists at NIAID's Vaccine Research Center (VRC) and their colleagues, will appear in the May 2 issue of Nature.
CD4+ T cells, also called "helper" T cells, are HIV's primary target. These cells help direct the immune system's response to various pathogens. HIV undermines the body's ability to protect against disease by depleting these cells.
From 12 HIV-positive individuals, the researchers isolated three subgroups of helper T cells: HIV-fighting cells, cytomegalovirus-fighting cells, and a "mixed" group. The scientists then examined these cells for evidence of HIV infection. In each case, HIV infected a much greater percentage of HIV-specific cells than cells in the other two groups. The cytomegalovirus-specific and mixed group showed no significant differences in HIV infection rates.
"For years we have known that the immune system does not produce a good CD4+ T cell response against HIV, and we have postulated that this might be because HIV preferentially infects HIV-specific CD4+ cells," says Richard Koup, M.D., senior study author and a senior investigator at the VRC. "This study is the first to show that this phenomenon actually happens in the body." Dr. Koup and his team tested two possible mechanisms underlying this phenomenon and found evidence for both.
The first occurs when the immune system initially confronts HIV. At this stage, HIV-specific CD4+ T cells are immature, or "na´ve." These young helper cells rapidly multiply into a mature HIV-fighting army, but they are exceptionally vulnerable to viral infection during this process. So the seeds of this HIV-fighting army of helper T cells might be infected from the start, Dr. Koup says, ensuring a perpetual high rate of infection among this group.
The researchers found laboratory evidence for this scenario. They exposed both na´ve and mature helper cells to HIV, then stimulated the na´ve cells to multiply through several rounds of cell division. The na´ve cells in their transitional state were infected at a much higher rate than the mature cells, Dr. Koup notes.
However, HIV infects mature as well as na´ve helper T cells. Another explanation for the high rates of infection among CD4+ T cells might be that the mature ones rush to the front lines of the body's battle against HIV and are therefore exposed to more of the virus than are cells that fight other pathogens.
To test this hypothesis, the researchers examined the cells of four HIV-positive individuals undergoing structured treatment interruption of their antiretroviral therapy. Because these individuals were past the early stage of infection, all their na´ve helper T cells had matured. When these patients went off antiretroviral drugs, their viral loads increased significantly, and their HIV-specific helper T cells tried to fight off the virus. Analysis showed that these cells became infected with HIV at a significantly higher rate than other helper T cells.
"This experiment shows that HIV continuously and preferentially infects mature HIV-specific helper T cells as they try to fight off the virus," say Dr. Koup. "In one patient, over half of all his infected CD4+ T cells were HIV-specific."
This finding means that clinicians should consider the possible negative consequences of structured therapy interruptions that allow virus levels to rebound, says lead study author Daniel Douek, M.D., Ph.D., chief of the VRC's Human Immunology Section. "Although short courses of structured intermittent therapy do not result in increased levels of HIV," he says, "longer regimens that permit the viral load to increase may result in long-term damage of the immune system's ability to fight off HIV."
The study also suggests ways to design a more effective HIV vaccine, Dr. Douek adds. Such a vaccine must induce a strong T-cell response against HIV. But because HIV-specific CD4+ T cells are especially vulnerable to HIV, an ideal vaccine should also create a broad and powerful CD8+ T cell response and antibodies against HIV, Douek explains. HIV does not infect CD8+ T cells, also known as cytotoxic or "killer" cells.
"A robust CD8+ response should be an important part of an HIV vaccine, and this is the strategy we pursue at the Vaccine Research Center," Dr. Douek says. "We are working on DNA 'prime-boost' vaccines. These two-part vaccines first prime the immune system with a shot of HIV DNA, then boost the immune response with a harmless viral vector that contains additional HIV genes. The boost enhances the CD8+ response."
NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
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