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Molecular switch may turn off immune
cells that target HIV
Report could lead to new understanding
of disease mechanism, potential new therapies
BOSTON - August 20, 2006 - One of the primary mysteries of
the AIDS epidemic - why the immune system is unable to control HIV
infection - may have been solved by an international research collaborative.
In an upcoming issue of Nature, the team reports how a molecular
pathway involved in the immune cell "exhaustion" that
characterizes several other chronic viral infections plays a similar
role in HIV infection. They also found that blocking the pathway
restores some function to HIV-specific CD8 and CD4 T cells. The
paper from researchers at the Partners
AIDS Research Center at Massachusetts General Hospital (MGH),
the University of
KwaZulu-Natal (UKZN) in South Africa, and other institutions
has received early online publication.
"Back in 1987 our MGH team confirmed the existence of HIV-specific
CD8 cells, the cytotoxic T lymphoctyes that should destroy virus-infected
cells," says Bruce Walker, MD, director of the Partners AIDS
Research Center (PARC) and principal investigator of the Nature
study. "But it didn't make sense that these cells were found
in high numbers in persons with late-stage disease (AIDS), indicating
that they were somehow not doing their job. These new findings finally
make sense out of our early discoveries and subsequent findings
by others in the field: The immune cells are there, but they have
been turned off in persons with high viral loads."
Several recent studies have shown that a molecular pathway involving
a receptor called PD-1 (Programmed Death-1) inhibits the immune
system in chronic viral infections - those in which the immune system
does not completely clear the virus. CD8 cells initially respond
to viral infection by reproducing dramatically and producing cytokines
that help destroy the viruses, but in chronic infection high levels
of virus appear to overwhelm and exhaust CD8 cells. Recent studies
in mice by Rafi Ahmed, PhD, of Emory University School of Medicine
and Gordon Freeman, PhD, of Dana-Farber Cancer Institute - both
co-authors of the current report - indicated that PD-1 is overexpressed
on these exhausted cells and may act as a molecular switch to turn
off their activity.
For the current study, designed to find whether a similar process
takes place in HIV infection, the US-based researchers worked closely
with collaborators from Durban, South Africa, an area where more
than 30 percent of the population is HIV-infected. They first examined
HIV-specific CD8 cells from 71 infected individuals who had not
yet begun antiviral therapy and found that PD-1 expression was indeed
higher on HIV-specific cells than on cells targeted against better
controlled viruses or on CD8 cells from uninfected individuals.
HIV-specific cells with high PD-1 expression also were less able
to divide and expand in response to HIV proteins. Relating PD-1
levels to key markers of HIV disease progression in the African
study participants turned up significant associations: increased
PD-1 expression correlated with increased viral load and reduced
levels of CD4 helper T cells.
To examine whether antiviral therapy might change the expression
of PD-1, the researchers examined blood samples taken from four
HIV-positive participants before and after they began antiretroviral
therapy. Along with the expected drop in viral load in response
to treatment, there was also a significant decrease in PD-1 expression
on HIV-specific CD8 cells, suggesting that elevated receptor expression
may be a response to the high viral loads of untreated individuals.
Using antibodies to block the PD-1 pathway in blood cells from infected
individuals significantly increased the ability of HIV-specific
CD8 cells to proliferate in response to viral antigens and also
increased the cells' production of the cytokine gamma interferon,
indicating improved function. Blocking the PD-1 pathway also increased
the proliferation of HIV-specific CD4 cells, and even cells from
individuals that previously had no detectable response had robust
proliferation after pathway blockade, indicated that cells that
had been turned off could be turned back on.
"It has been thought that the ineffectiveness of HIV-specific
T cells resulted from progressive, irreversible damage or bad cellular
'programming'," explains Daniel Kaufmann, MD, of PARC and the
MGH Infectious Disease Unit, a co-first author of the Nature paper.
"While this might still be partially the case, our finding
that defects in important functions of exhausted T cells can be
reversed demonstrates that active inhibitory mechanisms may play
a major role in blocking T cell function. In other words, the cells
may be turned off but not permanently disabled."
Co-first author Cheryl L. Day, PhD, agrees. "Natural regulatory
systems that help control the immune system appear to be shutting
it down before its work is done. One of the next questions we need
to answer is whether we can turn it back on for HIV-infected patients
in a way that will benefit them without incurring serious side effects."
Day is associated with the Doris Duke Medical Research Institute
at UKZN and the Partners AIDS Research Center.
"We could not have accomplished this work without our collaborators
in South Africa," says Walker. "We began our project there
believing we might find clues that could only be uncovered at the
heart of the epidemic, and this study bears that out. The ability
to conduct studies with large numbers of untreated people - who
are now receiving treatment at clinics we helped to establish -
allowed us to find the link between PD-1 expression and viral load."
Walker is a professor of Medicine at Harvard Medical School and
a Howard Hughes Medical Institute investigator.
Additional co-authors of the Nature paper are Photini Kiepiela,
PhD, Eshia Moodley, Sharon Reddy, Chantal DePierres, Zenele Mncube,
and Hoosen Coovadia, of the Doris Duke Medical Research Institute
at UKZN; Julia Brown, PhD, and Baogong Zhu, MD, of Dana-Farber Cancer
Institute; Elizabeth Mackey, Quentin Eichbaum, MD, PhD, and Marcus
Altfeld, MD, PhD, of PARC-MGH; Alasdair Leslie, PhD, Philip Goulder,
MD, PhD, and Paul Klenerman, MD, PhD, of Oxford University; Joseph
Miller, PhD, and Jaikumar Duraiswamy, PhD, of Emory University School
of Medicine; and E. John Wherry, PhD, of the Wistar Institute, Phildelphia.
The study was supported by grants from The Royal Society, the Harvard
University Center for AIDS Research, the Doris Duke Charitable Foundation,
the National Institutes of Health, the Howard Hughes Medical Institute,
the Foundation for the NIH through the Grand Challenges in Global
Health Initiative, and the Mark and Lisa Schwartz Foundation.
The Partners AIDS Research Center (PARC) was established in 1995
in response to the continuing worldwide AIDS pandemic. The center
serves both MGH and Brigham and Women's Hospital, the founding members
of Partners HealthCare, and is a natural progression of the more
than twenty-year commitment of the clinicians and scientists at
those institutions to HIV and AIDS research and care. The Doris
Duke Medical Research Institute at the University of KwaZulu-Natal
(UKZN) opened in 2003 and was established through a collaboration
between PARC-MGH and UKZN. The institute is focused on interdisciplinary
research into AIDS and other health issues affecting South Africa
and the entire African continent.
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 nearly $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, transplantation biology and photomedicine. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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