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Effective HIV control may depend on
viral protein targeted by immune cells
Specific protein targeted may be
more important than breadth of CD8 response
BOSTON - December 17, 2006 - An effective response of the
immune system's 'killer' T cells against infection with HIV may
depend on exactly which viral protein is targeted, according to
an international group of researchers. A new study finds that HIV-infected
individuals in whom virus-specific CD8 T cells are targeted against
the Gag protein have lower viral levels than do those with CD8 responses
directed against other viral proteins. The report from the Partners
AIDS Research Center at Massachusetts General Hospital (PARC-MGH),
the University
of Oxford and University
of KwaZulu-Natal in South Africa is receiving early online release
in Nature Medicine.
"Understanding which immune responses are effective in control
of HIV is of critical importance in vaccine development," says
Philip Goulder, MD, PhD, of PARC-MGH and Oxford, the senior author
of the study. "Previous approaches have focused on a 'more
is better' approach, seeking to generate responses against a broad
range of viral proteins, but these results challenge that dogma."
While many strategies for developing a vaccine to control HIV focus
on the activity of the CD8 T lymphocytes that recognize and destroy
virus-infected CD4 T cells, the fact that even patients in the last
stages of AIDS can have measurable CD8 responses indicates that
those responses are not always effective. To investigate how variations
in CD8 response alter the ability to control HIV, the research team
enrolled almost 600 South African patients who had not yet been
treated for their HIV infections.
The researchers comprehensively mapped the CD8 responses against
all viral proteins and also investigated whether the versions of
HLA Class I molecules involved in the immune system's recognition
of HIV protein fragments made a difference. When new viruses are
produced within an infected cell, Class I molecules grab viral fragments
and display them at the cell surface, thereby alerting CD8 cells
that the cell has been infected and should be destroyed. Earlier
studies, including a 2004
Nature report from the same group, showed that the genetically
determined version of an individual's HLA Class I molecules could
strongly influence immune control of HIV.
The current study found that only CD8 responses against the Gag
protein were associated with significantly reduced viral levels
and that individuals with responses against several different Gag
fragments had even lower viral loads. In contrast, those with stronger
responses against other HIV proteins - including Env, a protein
that is the focus of several vaccine studies - had higher viral
levels indicating poorer control of HIV.
In people receiving no antiretroviral treatment, the improved HIV
control associated with Gag-specific CD8 response would probably
translate into asymptomatic infection for more than a decade, compared
with progression to AIDS within two to three years of infection
in those with no Gag responses. The reason why patients' particular
HLA Class I molecules are linked to different HIV disease outcomes
now appears to be related to the number of Gag fragments displayed
by different versions of the Class I molecule.
Mechanisms underlying the different effects of the protein-specific
immune responses are unknown and require further investigation.
The researchers suggest that responses against proteins like Env
might be inherently less effective or might only be generated in
response to elevated viral loads. Therefore, the findings of this
study, which reflect chronic HIV infection, might not apply in situations
in which vaccination generates an immune response before infection
occurs.
"The possibility that there may be fundamental differences
between the impact of Gag and non-Gag CD8 responses on the ability
to control HIV has clear relevance to vaccine development,"
says Goulder, who is an associate professor of Medicine at Harvard
Medical School.
Co-authors of the Nature Medicine report from Doris Duke
Medical Research Institute at the University of KwaZulu-Natal are
first author Photini Kiepiela, Kholiswa Ngumbela, Christina Thobakgale,
Dhanwanthie Ramduth, Eshia Moodley, Shabashini Reddy, Chantal de
Pierres, Zenele Mncube, Nompumelelo Mkhwanazi, Karen Bishop, Mary
van der Stok, Kriebashnie Nair, Nasreen Kahn, and Hoosen Coovadia.
Other co-authors are Isobella Honeyborne, Hayley Crawford, Rebecca
Payne, Alasdair Leslie, Julia Prado, Andrew Prendergast, John Frater,
and Noel McCarthy, University of Oxford; Christian Brander and Bruce
Walker, Partners AIDS Research Center at Massachusetts General Hospital;
Gerald Learn, David Nickle, Christian Rousseau and James Mullins,
University of Washington School of Medicine; and David Heckerman,
Microsoft Research.
The study was supported by grants from the U.S. National Institutes
of Health, the Wellcome Trust, and the Mark and Lisa Schwartz Foundation.
Walker is a Howard Hughes Medical Institute investigator and a Doris
Duke Distinguished Clinical Science Professor, and Goulder is an
Elizabeth Glaser Pediatric AIDS Foundation Scientist.
The Partners AIDS Research Center (PARC) was established in 1995
in response to the continuing world-wide 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 by 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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