|
Study identifies key aspect of immune
response against HIV
Results illuminate evolutionary interaction
between virus and human immune system
BOSTON - December 8, 2004 - An international research team
has identified immune-system genes that appear to play a key role
in the body's defense against HIV, the virus that causes AIDS. The
findings may lead to ways of circumventing the virus's ability to
avoid vaccines by rapid mutation. The study in the Dec. 9 issue
of Nature also describes how HIV infection is driving human
evolution, since individuals with protective versions of the identified
genes are more likely to survive and pass those genes along to children.
Including researchers from the University
of Oxford and the University
of KwaZulu-Natal in South Africa, the investigation is a result
of a program established by the Partners
AIDS Research Center at Massachusetts General Hospital (MGH).
"This study identifies the genetic battleground where the struggle
between HIV and the human immune response occurs," says Philip
Goulder, MD, PhD, of the Partners AIDS Research Center at MGH, the
study's principal investigator. "The findings will help in
understanding precisely how the immune system can succeed or fail
against HIV, a prerequisite for a rational approach towards design
of an HIV vaccine." Goulder also has an appointment at the
Peter Medawar
Building for Pathogen Research at Oxford.
The human immune system learns to recognize and attack virus-infected
cells through the activity of human leukocyte antigen (HLA) Class
1 molecules, which sit on the surface of cells. When new viruses
are being produced within an infected cell, Class 1 molecules grab
fragments of viral proteins from within the cell and display them
at the cell surface, thereby alerting the body's "killer"
T cells that something foreign is within the cell and it should
be destroyed. Three genes called HLA-A, HLA-B, and HLA-C encode
Class 1 molecules, and it is known that the HLA-B genes are extremely
diverse, with more than 560 versions or "alleles" having
been identified. The current study was designed to test the theory
that the diversity of HLA Class 1 molecules could reflect differences
in the killer T cell activity controlled by those molecules.
The researchers analyzed blood samples from 375 HIV-infected patients
at the Doris
Duke Medical Research Institute at the University of KwaZulu-Natal
to determine whether particular HLA Class 1 molecules control the
killer T cell response against the virus. They found that an individual's
version of HLA-B made a significant difference in how well the immune
system responds against HIV, whereas the version of HLA-A or HLA-C
inherited did not matter.
To examine the impact of Class 1 molecules on blood viral levels,
the team studied more than 700 chronically infected African patients
and again found that particular versions of HLA-B were associated
with high or low plasma virus levels. Additional tests that looked
at levels of the helper T cells that are destroyed by HIV and that
analyzed samples from Australian patients infected with a different
strain of virus all supported the conclusion that the form of the
HLA-B molecule patients inherit makes a significant difference in
how well their immune systems cope with HIV infection.
Evidence of the virus's impact on human evolution was found in an
analysis of HLA-B alleles in HIV-infected mothers and their infants.
Not only are HIV-infected women who have a protective version of
HLA-B more likely to survive, they are also less likely to pass
the virus along to their children. From an evolutionary standpoint,
that finding suggests a trend towards greater frequency of the protective
alleles in a population over time.
"We have known for some time that HLA-B molecules are evolving
more rapidly than other types, but it has been unclear why this
is happening," says Goulder. "These data suggest an explanation
for the more rapid evolution of HLA-B in response to other infectious
diseases, not only HIV. This is an exciting time for infectious
disease research because we are witnessing the evolutionary fight
between the human immune system and the HIV virus happening right
now, rather than over a period of thousands of years." Goulder
is an assistant professor of Medicine at Harvard Medical School.
"The AIDS crisis will only be solved with the development of
an effective vaccine," says Bruce Walker, MD, director of the
Partners AIDS Reseach Center at MGH and a co-author of the current
study. "This study's results help to focus this effort by telling
us what the most effective immune responses are." Walker is
also a Howard Hughes Medical Institute researcher and a professor
of Medicine at Harvard Medical School.
In addition to Goulder and Walker, authors of the Nature
study are first author Photini Kiepiela, and Isobella Honeyborne,
Danni Ramduth, Christina Thobakgale, Senica Chetty, Prenisha Rathnavalu
and Hoosen Coovadia of the Doris Duke Medical Research Institute
at UKZN; Alasdair Leslie, Katja Pfafferott, Louise Hilton, Peter
Zimbwa, Cheryl Day, and Paul Klenerman of the Medawar Building for
Pathogen Research at Oxford; Corey Moore, Ian James and Simon Mallal
of Royal Perth Hospital in Australia; Sarah Moore, University of
Washington; Michael Bunce, Dynal Biotech Ltd, Wirral, UK; Linda
Barber, Royal Free Hospital, London; Bette Korber, Santa Fe Institute;
and Todd Allen, Christian Brander, Marylyn Addo, and Marcus Altfeld
of the Partners AIDS Research Center at MGH. The study was supported
by grants from the National Institutes of Health, the Doris Duke
Charitable Foundation, the Wellcome Trust, and the Elizabeth Glaser
Pediatric AIDS Foundation.
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 more than $400 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Grace
Haydon, University of Oxford
Smita
Maharaj, University of KwaZulu-Natal
Physician Referral Service: 1-800-388-4644
Information about Clinical Trials
|
|
 |
