Date Published:
3 November 2006 |
Early-stage immune system control of HIV may depend on inherited factors
Findings may provide important clues for vaccine development
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.
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