First Genome-Wide Study of Infectious Disease
Opens New Avenues for HIV Treatment, Vaccines
The first genome-wide association study of an infectious disease,
conducted by an international group of researchers through the
Center for HIV/AIDS Vaccine Immunology (CHAVI), has yielded a new
understanding of why some people can suppress virus levels following
HIV infection. “The clearer picture of host responses to the virus
achieved through this examination of genomes could lead to improved
HIV therapies and provides new targets for vaccine developers,” says
Elias A. Zerhouni, M.D., director of the National Institutes of
Health (NIH). CHAVI, which is led by Barton Haynes, M.D., of Duke
University, Durham, N.C., was established in 2005 by the National
Institute of Allergy and Infectious Diseases (NIAID), part of the
NIH.
CHAVI’s host genetics team, led by David Goldstein, Ph.D., also
of Duke University, included scientists from several European countries
and Australia who formed a consortium, EuroCHAVI, to perform this
study. The investigators identified three gene variants, two of
which are linked to an infected person’s ability to control HIV
viral load and a third that is implicated in disease progression
to AIDS. The research is being published by Science on the Science Express
Web site on Thursday, July 19.
“CHAVI is designed to foster collaborative research to overcome
roadblocks that have impeded HIV vaccine development,” says NIAID
Director Anthony S. Fauci, M.D. “The insights into genetic factors
influencing host control of HIV revealed by this work exemplify
the power of such collective investigations.”
Genome-wide association studies aim to identify genetic variations
among people that can be tied to variations in disease susceptibility.
Recent genome-wide association studies have found genetic markers
linked to increased risk of such ailments as diabetes, cancer and
heart disease. The CHAVI investigators are the first to apply genome-wide
association techniques to an infectious disease.
“People vary greatly in their vulnerability to HIV infection,” notes
Dr. Haynes. “In particular, there are striking and largely unexplained
differences between individuals in the degree to which they are
able to hold viral levels to a low set point in the period soon
after infection.” If scientists could pinpoint the gene variants
that help some people control HIV infection — or avoid it
altogether — they might be able to rationally design therapies
or vaccines to mimic these naturally occurring genetic advantages,
he notes.
In 2006, CHAVI researchers launched an effort to pool genetic
data from HIV-positive individuals who had enrolled in nine studies
based throughout Europe and in Australia. Together, these studies
contained information on more than 30,000 individuals. From this
pooled cohort, the CHAVI scientists ultimately chose 486 DNA samples — representing
the genomes of 486 HIV-positive people whose viral load set points
had been carefully and accurately measured at multiple time points — for
the genome-wide association study.
The scientists applied the genome samples to gene chips dotted
with more than 550,000 human gene variants, called single nucleotide
polymorphisms or SNPs. The sweep of genomes found three SNPs that
were strongly associated with either viral load set point or disease
progression. The two variants associated with viral load can explain
15 percent of the total variation among all infected individuals,
the scientists estimate.
One of the identified variants is near a human immune gene called HLA-C,
and may provide a new route for HIV vaccine developers to explore,
says Dr. Goldstein. People with the identified variant are thought
to make more of the gene’s product than people who lack this presumably
protective genetic variant. A consequence of this extra production
of HLA-C protein, researchers hypothesize, is that the immune system
is better able successfully identify and remove HIV-infected cells,
thus keeping viral load set points low for long periods.
HIV has many ways to defend itself from immune system efforts
to eliminate it. One defense is the ability of an HIV gene, nef,
to decrease the production of two related immune system proteins,
HLA-A and HLA-B. Nef, scientists believe, is not able
to similarly hamper the expression of HLA-C. If scientists
could design a vaccine to enhance HLA-C-mediated immune responses,
they might be able to hit HIV at a vulnerable point, says Dr. Goldstein.
Although HLA-C had previously been suspected of contributing to
HIV control, this genome-wide study is the first to confirm the
association, he adds.
The CHAVI investigators are currently building on these studies
of polymorphisms to pinpoint the specific human gene variants that
influence HIV replication.
“We applaud the CHAVI investigators for the highly collaborative
nature of this work. It demonstrates that answers to important
questions, requiring analysis of large amounts of clinical specimens,
can be obtained quickly,” says Peggy Johnston, Ph.D., director
of NIAID’s Vaccine Research Program.
CHAVI is a consortium of researchers from five institutions. In
addition to Duke University, the institutions are the University
of North Carolina — Chapel Hill; the University of Alabama — Birmingham;
Harvard Medical School, Boston, Mass.; and Oxford University, U.K.
NIAID established CHAVI in response to recommendations made by
the Global HIV Vaccine Enterprise, and its goals are linked to
those of the Enterprise. Endorsed by world leaders at a G-8 summit
in June 2004, the Enterprise is a virtual consortium of independent
organizations committed to accelerating development of effective
vaccines against HIV/AIDS through the creation and implementation
of a shared strategic scientific plan, mobilization of resources,
and greater coordination among HIV vaccine researchers worldwide.
Additional information about the Global Enterprise can be found
at http://www.hivvaccineenterprise.org/.
For additional information about CHAVI, visit http://www.chavi.org/.
NIAID is a component of the National Institutes of Health. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research on basic immunology,
transplantation and immune-related disorders, including autoimmune
diseases, asthma and allergies. News releases, fact sheets and
other NIAID-related materials are available on the NIAID Web site
at http://www.niaid.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
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