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Early-stage immune system control of
HIV may depend on inherited factors
Findings may provide important clues
for vaccine development
BOSTON - November 3, 2006 - How well an individual's immune
system controls HIV during the earliest phases of infection appears
to depend on both the specific versions of key immune-system molecules
called HLA Class I that have been inherited and on the fragments
of viral protein those molecules display to the T lymphocytes that
usually destroy infected cells. In a report in the November issue
of PLOS Medicine, researchers from the
Partners AIDS Research Center at Massachusetts General Hospital
(PARC/MGH) report that specific HLA Class I/HIV viral fragment combinations
are associated with a more powerful antiviral response, findings
that may help develop vaccines against HIV.
"We found that only a limited number of viral protein fragments
from HIV-1 are targeted by the immune system in early infection
and that the versions of HLA Class I previously associated with
slower HIV-1 disease progression also contribute more to this initial
antiviral immune response," says Marcus Altfeld, MD, PhD, of
PARC/MGH, the paper's lead author.
An essential aspect of the immune response involves educating T
cells to recognize pathogens or other "non-self" proteins.
This is done by means of human leukocyte antigen (HLA) receptors
that sit on the surface of virtually every cell. Immune system cells
that ingest bacteria or parasites digest those pathogens and display
protein fragments on their surface membranes via HLA Class II proteins.
Virally infected cells display viral proteins on HLA Class I molecules,
which activate the CD8 cytotoxic T lymphocytes that usually destroy
infected cells. Although the CD8 response against HIV is ultimately
ineffective in protecting infection, several studies have suggested
that it plays a key role in determining how quickly the disease
progresses after initial infection.
HLA - also called major histocompatibility complex (MHC) - proteins
are also the primary markers of tissues as "self." Unique
to each individual, these are the factors that need to be matched
as closely as possible in organ transplants, with perfect matches
only possible between identical twins. Some studies have found that
HIV patients with particular versions of HLA may be better able
to control viral levels, but the diversity of HLA molecules - each
person may have up to six different varieties of Class I proteins
- has made investigating the role of HLA type in HIV infection challenging.
The current study was designed to determine the contribution of
both HLA Class I and the particular viral fragments displayed on
those molecules to the activation of HIV-specific CD8 cells. The
researchers analyzed blood samples from more than 100 people recently
infected with HIV, first determining their specific HLA types by
DNA analysis. Then they focused on 173 HIV protein fragments known
to bind to those HLA types to see if particular peptides were more
powerful in activating the HIV-specific CD8 response.
The researchers found that, for many varieties of HLA, only a few
HIV protein fragments were responsible for the activation of CD8
T cells early in infection. In addition, the same HLA types that
had been previously identified in people who stay healthy for a
longer period of time after initial infection were associated with
a more powerful early-stage HIV-specific CD8 activity.
"While we can't say this for sure right now, it is looking
like both the HLA Class I molecule and the specific viral sequences
being displayed contribute to the strength of immune response against
primary HIV infection," says Altfeld. "In addition, the
combination of Class I molecules that an individual expresses, something
that is genetically determined, seems to have a significant impact
on the specificity and strength of that response.
"Identifying the HIV epitopes [viral fragments] that are particularly
good at priming an early T cell response may be important to vaccine
design, and the impact of an individual's genetic HLA Class I background
implies that a successful vaccine would have to overcome genetic
factors associated with a less protective response," he adds.
Altfeld is an associate professor of Medicine at Harvard Medical
School. He and his colleagues are working on a follow-up study with
samples from 500 individuals to further investigate the impact of
HLA Class I on the control of HIV replication.
The study was supported by grants from the National Institutes of
Health and the Doris Duke Charitable Foundation, with additional
support from the National Cancer Institute and the Center for Cancer
Research. In addition to senior author Bruce Walker, MD, director
of the Partners AIDS Research Center at Massachusetts General Hospital,
the report's co-authors are Elizabeth Kalife, Hendrik Streeck, MD,
Mathias Lichterfeld, MD, Mary Johnston, Nicole Burgett, Martha Swartz,
Amy Yang, Galit Alter, PhD, Xu Yu, MD, Angela Meier, MD, Todd Allen,
PhD, and Eric Rosenberg, MD, of PARC/MGH; Ying Qi and Mary Carrington,
PhD, of the National Cancer Institute, Heiko Jessen, MD, Gemeinschaftspraxis
Jessen, Berlin; and Juergen Rockstroh, MD, PhD, University of Bonn,
Germany.
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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