May 26, 1998
Current theories hold that HIV propagates itself through rapid, continuous cycles of infection and death of activated CD4+ T cells, the virus primary target. In the May 26, 1998, issue of the Proceedings of the National Academy of Sciences, William E. Paul, M.D., of the National Institute of Allergy and Infectious Diseases (NIAID), and colleagues argue that so-called latently infected cells, in which the virus lies in a quiescent state, also feed the "fire" of HIV infection.
"This is an interesting report that could help explain recent findings regarding the persistence of HIV reservoirs, and evidence of replicating HIV, in individuals whose viral loads have been driven to undetectable levels with anti-HIV drugs," says NIAID Director Anthony S. Fauci, M.D. "It also raises important questions for future studies."
"Productively infected CD4+ T cells provide a fast-burning fuel for HIV replication," explains Dr. Paul, chief of NIAIDs Laboratory of Immunology. But sustaining HIV infection with this fuel alone, he adds, would require continuously high concentrations of HIV. In most infected individuals, the amount of circulating virus declines rapidly after reaching peak levels soon after initial infection.
Dr. Paul and his co-authors, Zvi Grossman, Ph.D., of Tel Aviv University in Israel, and Mark B. Feinberg, M.D., of Emory University in Atlanta, Ga., believe a second kind of fuel slow-burning but persistent is essential for maintaining active infection after HIV levels decline. The scientists assert that both long-lived, latently infected cells and chronically infected cells provide this fuel. They hypothesize that, during acute HIV infection, the lymphoid tissues of the immune system are seeded with chronically and latently infected cells. These cells spark local bursts of infection when CD4+ T cells in their immediate vicinity become activated, a process they call proximal activation and transmission, or PAT.
"Given what we know about the interaction of HIV with its target cells," says Dr. Paul, "we believe PAT provides the most plausible explanation of HIV propagation during chronic infection." To support HIV replication, he explains, CD4+ T cells must first be activated. Activation events are typically local and transient, occurring in microscopic sites within lymphoid tissues in the form of cell proliferation bursts that last several days and then subside. One reason why these bursts subside is due to the phenomenon of anergy, or partial immune unresponsiveness, that is induced in many T cells of HIV-infected inviduals. Anergic T cells are unable to become fully activiated and thus are unable to support HIV infection.
"Studies have shown that T cells activated in the presence of a cellular source of HIV are much more likely to become infected than are activated cells simply exposed to the ambient HIV in extracellular fluid," says Dr. Paul. "This would be particularly true when viral burdens are low, since contact between virus and activated cells would be less likely." In the PAT model, the time contingency of activation and virus transmission, he adds, may even render the target cells more susceptible and the virus more infective, since cell-free HIV is believed to rapidly lose infectivity.
Dr. Paul notes that the PAT model implies that low levels of HIV replication may be maintained in individuals who have no detectable HIV in their blood as a result of combination antiretroviral therapy. Several groups of researchers, including one led by Dr. Fauci, have found reservoirs of latently infected cells in such individuals. In their study, reported late last year, Dr. Fauci and colleagues in NIAIDs Laboratory of Immunoregulation detected unintegrated HIV DNA, a sign of HIV replication, in these cells.
Dr. Paul and his colleagues also believe PAT could have important implications for HIV vaccine research. "If the initial seeding of tissues with latently infected cells is essential for a sustained chronic infection," says Dr. Paul, "then a major focus in developing vaccines should be on those parameters and molecular events that facilitate latent infection. These parameters are presently poorly understood."
Dr. Paul recently served as director of the National Institutes of Healths (NIH) Office of AIDS Research (OAR). Drs. Grossman and Feinberg served with Dr. Paul in the OAR prior to assuming their current positions.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
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