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 NIAID's 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
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
NIAID's 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
Dr. Paul recently served as director of the National Institutes of
Health's (NIH) Office of AIDS Research (OAR). Drs. Grossman and
Feinberg served with Dr. Paul in the OAR prior to assuming their current
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