- 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.
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- "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.
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- 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.
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- >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.
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- "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.
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- The first occurs when the immune system initially confronts
HIV. At this stage, HIV-specific CD4+ T cells are immature, or "naïve."
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.
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- The researchers found laboratory evidence for this scenario.
They exposed both naïve and mature helper cells to HIV, then stimulated
the naïve cells to multiply through several rounds of cell division.
The naïve cells in their transitional state were infected at a much
higher rate than the mature cells, Dr. Koup notes.
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- However, HIV infects mature as well as naïve 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.
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- 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 naïve 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.
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- "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."
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- 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."
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- 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.
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- "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."
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- 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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- 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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- Reference: D Douek et al. HIV preferentially infects
HIV-specific CD4+ T cells. Nature 417(6884):95-98 (2002).
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- Editor's Note: The original news release can be found
at http://www.nih.gov/news/pr/may2002/niaid-01.htm
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- Note: This story has been adapted from a news release
issued by NIH/National Institute Of Allergy And Infectious Disease for
journalists and other members of the public. If you wish to quote from
any part of this story, please credit NIH/National Institute Of Allergy
And Infectious Disease as the original source. You may also wish to include
the following link in any citation: http://www.sciencedaily.com/releases/2002/05/020503075625.htm
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