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Study finds HIV protein can drive immune
cells away
Clue to how virus avoids immune system
activity may lead to new treatment strategy
BOSTON - May 3, 2004 - Massachusetts General Hospital (MGH)
researchers may have provided another clue to the mystery of how
HIV, the virus that causes AIDS, evades the defenses of the immune
system. In the May issue of the Journal of Virology, a team
from the Partners
AIDS Research Center at MGH describes finding how a key protein
that helps the virus enter its target T helper cells may also keep
away the T killer cells that should destroy HIV-infected cells.
"One of the big questions in understanding HIV is why we can
see immune responses that are effective in the test tube but do
not eradicate the virus in the infected patient," says Mark
Poznansky, MD, PhD, of the Partners AIDS Research Center (PARC)
and the MGH Infectious Disease Unit, the paper's senior author.
"We have identified a potential new mechanism by which pathogens
can repel immune cells and thereby evade the immune system."
In 2000, Poznansky and colleagues published
a report that found how a protein called SDF-1, known to attract
immune cells, can actually repel T cells when present in elevated
quantities. SDF-1 is a chemokine, a protein normally produced to
summon immune cells to the site of an injury or infection. The molecule
is known to interact with a T cell receptor called CXCR4 which also
is used by HIV when it binds to and enters T helper cells. Investigating
whether HIV infection involves the same kind of cellular repulsion
observed in the earlier study - a process the researchers dubbed
"fugetaxis" - seemed a logical next step.
In a series of experiments led by Diana Brainard, MD, a research
fellow in Poznansky's lab, the team first found that while low concentration
of gp120, the HIV protein that interacts with CXCR4, attracted T
killer cells, higher concentrations induced the immune cells to
move away. They then showed that it was the specific interaction
of gp120 with CXCR4 that controlled T cell movement, and that the
same repulsion could be produced specifically with T killer cells
programmed to attack HIV.
The researchers then used immunized mice to look at the effects
of the viral protein in vivo. One day after the mice were injected
with an antigen to which they had been previously immunized, they
received an additional injection of either low- or high-dose recombinant
gp120 protein or saline as a control. For up to 24 hours afterwards,
mice receiving the high-dose gp120 were found to have a significantly
lower immune response to the antigen injection than either control
mice or those that had received the low-dose gp120.
"This is the first report of fugetaxis caused by a viral gene
product and could be an important way that HIV keeps the immune
system at bay," Poznansky says. "We don't know yet if
this process occurs in patients infected with HIV, but if it does,
it provides a new therapeutic approach that could block this viral
protein activity and allow immune cells to do their job."
Brainard and Poznansky add that this mechanism could also be used
by other viruses - including the pox viruses, papilloma viruses
and herpes viruses - that remain in the body after initial infection
and have proteins known to influence cellular movement. Poznansky
is an assistant professor of Medicine at Harvard Medical School.
Additional co-authors are William Tharp, Elva Granado, Nicholas
Miller, Alicja Trocha and Bruce Walker, MD, of MGH/PARC; Xiang-Hui
Ren, MD, and Ernest Terwilliger, PhD, of Beth Israel Deaconess Medical
Center; Brian Conrad, University of Michigan; and Richard Wyatt,
Dana Farber Cancer Institute. The work was supported by grants from
the U.S. Public Health Service and the American Foundation for AIDS
Research.
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 $400 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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