New research suggests that HIV-specific T cells persist in infected individuals,
but high virus levels can diminish the ability of those cells to respond to
infection. The report sheds new light on how HIV evades the immune system
and establishes long-term infections. The research appears in the November
20, 2001 issue of the Proceedings of the National Academy of Sciences.
"HIV infection not only destroys the body's resistance to other pathogens,
but it can manipulate the immune system for its own survival," says Anthony
S. Fauci, M.D., director of the National Institute of Allergy and Infectious
Diseases (NIAID). "This research provides some important clues to how
the virus accomplishes that goal."
In chronic viral infections, CD4+ T cells are required for the immune system
to keep virus levels in check. In HIV-infected people, however, few anti-HIV
CD4+ T cells proliferate when exposed to viral proteins. Researchers have
not known if the absence of a proliferative T-cell response occurs because
the virus destroys or merely inactivates HIV-specific CD4+ T cells.
NIAID's Andrew McNeil, M.D., and Mark Connors, M.D., led a study to answer
that question. The investigators studied the T cells of three groups of patients:
those with progressive HIV infection; a rare subset of individuals with long-term,
untreated infection but with viral RNA levels consistently below the level
of detection (long-term nonprogressors); and patients on antiretroviral therapy
who stopped taking their drugs long enough for virus levels to rebound.
All three groups had equal numbers of HIV-specific CD4+ T cells, indicating
the cells were not destroyed by the virus. The HIV-specific CD4+ T cells of
people with progressive disease, however, did not respond to the virus by
proliferating, suggesting they had somehow been turned off.
To examine the cause and effect relationship between proliferative T-cell
responses and immune control over the virus, Drs. McNeil, Connors, and their
colleagues turned to the patients who showed anti-HIV T-cell proliferation
while taking antiretroviral drugs. The investigators reasoned that if those
T cells were keeping HIV levels low, they should continue to do so even if
therapy were interrupted. When the researchers stopped the drugs, however,
virus levels rebounded in each of the patients. In those individuals, anti-HIV
CD4+ T cells were present but lost their ability to proliferate as virus levels
increased. Furthermore, the cells maintained their inactive state until antiretroviral
drugs brought virus levels back under control.
The results suggest that the loss of HIV-specific T-cell proliferation may
not be a cause, but rather is an effect, of high virus levels. Such proliferation,
which is present in long-term nonprogressors, therefore does not necessarily
predict immune control over the virus.
"This presents a good news/bad news scenario," says Dr. Connors.
"The good news is that HIV-specific CD4+ T cells are not completely deleted;
the bad news is that measuring the activity or even the frequency of those
cells is not necessarily a good predictor of long-term virus control."
The results suggest that long-term interruptions in antiretroviral therapy
may not be the best way to stimulate anti-HIV immune responses. The results
also provide some clues to how HIV disrupts the immune response to itself
and responses to other pathogens.
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, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
Press releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.
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