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Exhaustion of HIV-specific T cells
may be caused by chronic exposure to virus
Better understanding of immune
response to virus required for vaccine development
BOSTON - May 5, 2008 - The "exhaustion" of immune
cells that target HIV appears to result from chronic exposure to
the virus, specifically exposure to the particular protein segments
targeted by the pathogen-killing HIV-specific CD8 T cells. A study
from researchers at the Partners
AIDS Research Center at Massachusetts General Hospital (PARC-MGH),
appearing in the May issue of the open-access journal PLoS Medicine,
may have answered a key question regarding the immune response to
HIV infection: is the functional impairment of HIV-specific cytotoxic
T lymphocytes (CTLs) the cause or the result of unchecked viral
replication in chronic progressive HIV-1 infection?
"Although we know that CTLs can control replication of HIV,
we still don't know which particular features of the CTL response
are key to this control," says Hendrik Streeck, MD, of PARC-MGH,
the paper's lead author. "Better understanding how the quality
of the T-cell response changes during HIV infection will be necessary
for the design of effective T-cell-based vaccines against HIV."
Previous research has shown that, in most HIV-infected individuals,
HIV-specific CTLs gradually lose their ability to proliferate and
secrete the cell-killing substances called cytokines as infection
proceeds. In parallel, the immune system's ability to control viral
replication diminishes over time. It was not clear, however, whether
the exhaustion of HIV-specific CTLs was caused by or resulted from
persistent viral replication. The PARC-MGH team study was designed
to address that very issue.
The study enrolled 18 participants who had recently become infected
with HIV. Antiviral treatment was started in 7 participants, while
11 remained untreated during the study period. During the following
months, the researchers monitored participants' viral loads and
also analyzed the ability of their CTLs to respond to the specific
viral protein segments against which the cells were targeted. In
participants who received antiviral treatment, viral loads quickly
dropped to undetectable levels, and HIV-specific CTLs maintained
or even improved their response against their target proteins during
the four month after study enrollment.
Viral loads in untreated participants gradually rose during the
eight months after enrollment, and during that time HIV-specific
CTLs gradually lost functional capacity. To further investigate
the interaction between CTLs and their target viral peptides, researchers
examined what happened when target peptides mutated and were no
longer recognized by the T cells. In that situation, CTLs specific
for the original version of the mutated peptides regained their
functional capacity, but CTLs targeted against unchanged peptides
continued in an exhausted state. These results support the theory
that it is persistent contact with the peptide antigen that leads
to CTL exhaustion.
"To understand what's happening in any battle, you need to
know what's going on with the soldiers as well as with the enemy,
so investigating the nature of CTL responses in HIV infection requires
monitoring both virus and host responses simultaneously," Streeck
says. "Therefore, it is important that HIV vaccine trials evaluate
the immune responses carefully in the context of the virus, as the
virus might already have evolved. The inability of the vaccine-induced
immune response to cross-recognize the infecting virus might actually
have contributed to the failure of recent HIV vaccine trials."
Streeck is a research fellow in Medicine at Harvard Medical School.
The senior author of the PLoS Medicine report is Marcus
Altfeld, MD, PhD, of PARC-MGH. Additional co-authors are Zabrina
Brumme, PhD, Kristin Cohen, Jonathan Jolin, Angela Meier, MD, Chanson
Brumme, Eric Rosenberg, MD, Galit Alter, PhD, Todd Allen, PhD and
Bruce Walker, MD, of MGH-PARC, and Michael Anastario, PhD, Uniformed
Services University of the Health Sciences. The study was supported
by funding from the National Institutes of Health, the German Academic
Exchange Service, and the Canadian Institutes of Health 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 $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 photomedicine.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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