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Second pathway behind HIV-associated
immune system dysfunction identified
Potential treatment target
needs further investigation before clinical testing
BOSTON - September 30, 2007 - Researchers at the Partners
AIDS Research Center at Massachusetts General Hospital (PARC-MGH)
may have discovered a second molecular "switch" responsible
for turning off the immune system's response against HIV. Last year
members of the same team identified a molecule
called PD-1 that suppresses the activity of HIV-specific CD8
T cells that should destroy virus-infected cells. Now the researchers
describe how a regulatory protein called CTLA-4 inhibits the action
of HIV-specific CD4 T cells that control the overall response against
the virus. The report will appear in the journal Nature Immunology
and is receiving early online release.
"We've shown that a known regulator of the immune system, CTLA-4,
is present in elevated levels on the virus-specific CD4 cells that
should be managing the body's response against HIV, says Daniel
Kaufmann, MD, of PARC and the MGH Infectious Disease Unit, a co-first
author of the paper. "We also found that CTLA-4 expression
rises as HIV infection progresses and that the molecule switches
off CD4 cell function in a way that appears to be reversible."
Expression of the CTLA-4 protein is known to be elevated on activated
T cells, those that have encountered a pathogen and are multiplying
rapidly to mount an immune response. Studies in cancer patients
have shown that the molecule serves to dampen the immune response,
and some preliminary investigations in animals and humans have suggested
a potential role in HIV infection. The current study was designed
to examine how CTLA-4 may be involved in the dysfunction of HIV-specific
T cells that leads to the immune-system breakdown of AIDS.
The researchers first found that CTLA-4 was overexpressed on the
HIV-specific CD4 T cells of infected individuals who had not yet
received antiviral treatment. Levels were highest in those with
symptoms of acute infection and second highest in chronically infected
participants. CTLA-4 expression was lowest among a group of participants
whose immune systems were naturally able to suppress HIV replication
without antiviral medications - "elite controllers" in
whom viral levels are too low to be detected.
Elevated CTLA-4 expression also correlated with signs of disease
progression - increased viral load and reduced overall CD4 count.
While antiviral treatment caused viral loads to drop significantly
after treatment began, it resulted in only modest and slow drops
in CTLA-4 expression. In vitro tests of the effects of blocking
the CTLA-4 molecule improved the function of HIV-specific CD4 cells.
Comparing the effects of blocking CTLA-4 with those of blocking
PD-1 or both molecules produced functional improvements that varied
considerably between participants, signifying a complex relationship
between the pathways controlled by the two molecules.
"Both of these pathways contribute to dysfunction of HIV-specific
T cells and both may be considered targets for therapeutic intervention.
But since their mechanisms are so complicated, further study is
needed before clinical trials can be planned," says Kaufmann,
an instructor in Medicine at Harvard Medical School (HMS).
"Understanding why the immune system fails to control HIV is
essential for development of vaccines and new therapies" said
Bruce Walker, MD, director of PARC-MGH and senior author of the
study. "These studies suggest that the immune system is turning
itself off prematurely in HIV-infected persons, and the big challenge
now is to figure out if we can turn it back on, getting it to do
what it is supposed to do, without causing collateral damage in
the process." Walker is a professor of Medicine at HMS and
a Howard Hughes Medical Institute (HHMI) investigator.
Co-first author of the Nature Immunology report is Daniel
Kavanagh, PhD, also of PARC and MGH. Additional co-authors are Florencia
Pereyra, MD, Elizabeth Mackey, Toshiyuki Miura, PhD, DM; Mark Brockman,
Almas Rathod, Alicja Piechocka-Trocha, Brett Baker, Sylvie Le Gall,
PhD, Michael Waring, Ryan Ahern, Kristen Moss, and Eric Rosenberg,
MD, of PARC-MGH; John Zaunders and Anthony Kelleher, MBBS, PhD,
St. Vincent's Hospital, Darlington, NSW, Australia; Sarah Palmer,
PhD, and John Coffin, PhD, National Cancer Institute; Baogong Zhu,
MD, and Gordon Freeman, PhD, Dana-Farber Cancer Institute. External
support for the study came from the National Institutes of Health,
Howard Hughes Medical Institute and the Mark and Lisa Schwartz Foundation.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicin
.
Media Contacts: Valerie
Wencis, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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