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Genomic Analysis Uncovers New Targets for HIV Vaccine

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Duke Health News 919-660-1306

DURHAM, N.C. – An international team of researchers has
identified three gene variants in the DNA of 486 people
infected with HIV that appear to have helped some of the
patients fight off the virus and delay the onset of full-blown
AIDS.

The researchers expect the new findings to aid the search
for an HIV vaccine that would work by boosting the protective
effects of one or more of these genes, and help the body's own
immune system overcome an infection. One of the genes looks
particularly attractive as a vaccine target.

The study, published early online by the journal Science
July 19, was directed by David Goldstein,Ph.D., at Duke
University and is the first large cooperative study with major
findings arising from the Center for HIV/AIDS Vaccine
Immunology, (CHAVI) a seven-year project funded by the National
Institute of Allergy and Infectious Diseases, part of the
National Institutes of Health, in 2005, led by Duke's Barton
Haynes, M.D.

It took the international genetics team, called EuroCHAVI,
pooling their cohorts of carefully selected patients and using
the latest in genome-wide screening technology, 18 months to
discover the three genes, that together greatly increase our
knowledge of why patients differ in how well they can control
the virus that causes AIDS.

These findings represent only the first of what
investigators said will be a series of future genome-wide
studies to pinpoint additional targets for HIV vaccines. In the
new analysis, patients with specific gene variants in key
immune system cells appear to be much better at controlling the
proliferation of the virus after infection. These gene variants
are known as polymorphisms.

"These results not only approximately double our
understanding of the factors that influence variation amongst
individuals in how they control HIV-1, but also point torward
new mechanisms of control," said Goldstein, director of the
Center for Population Genomics and Pharmacogenetics at Duke's
Institute for Genome Sciences
& Policy
. Goldstein is the senior author of the
paper.

"As we expand the number of patients in future studies
conducted by CHAVI researchers, we aim to discover even more
polymorphisms that could provide additional clues how some
patients are better able to control the virus than others,"
Goldstein. "This should ultimately lead to novel targets for
vaccines, the primary goal of CHAVI."

Two of the polymorphisms found were in genes controlling the
human leukocyte antigen (HLA) system, which plays a major role
in the immune system by identifying foreign invaders and
"tagging" them for destruction.

Two of the HLA genes, known as HLA-A and B, are turned off
by HIV when it enters the body, which keeps the immune system
from recognizing the virus as foreign. HLA-C however is not
thought to be turned off by HIV-1. The new results suggest that
for some individuals at least HLA-C is involved in controlling
HIV-1. Since HIV-1 appears unable to shut off HLA-C, unlike A
and B, HLA-C may represent an Achilles heel of HIV, according
to Goldstein, who said that a vaccine could be designed to
elicit an HLA-C mediated response which HIV-1 might be unable
to defuse.

"This study was the first time a genome-wide approach has
been used for an infectious disease," Goldstein said. "Past
studies have looked at individual candidate genes. Since
different people respond differently to infections, a better
understanding of how immune system genes control responses to
infections should help us to design better treatments and more
effective vaccines."

Added Haynes: "CHAVI was designed to do big science, and the
results of this analysis represent just the first of what
should be many advances. The technology used and collaborative
efforts involved were truly remarkable: together as a group we
were able to do something that none of us individually could
accomplish. The results of this and future CHAVI studies should
help individual laboratories across the world perform research
to better understand the virus."

When someone becomes infected with HIV, the amount of virus
in the blood spikes as the virus multiplies. After this peak,
the amount of virus in the blood, known as the viral load,
gradually decreases and then levels off, a period during which
patients do not exhibit symptoms of their disease. The viral
load during this leveling out is an indication of how well the
patients' own immune system is battling the virus, and this is
the point in the infection's natural history that the
researchers studied.

The CHAVI investigators wanted to study those patients who
had many sequential blood samples taken during this plateau in
viral load. Before their analyses began collaborators in the
EuroChavi consortium, coordinated by Amalio Telenti at the
University of Lausanne, sifted through data collected from more
than 30,000 patients who had blood samples taken as a part of
nine studies in Europe and Australia. They arrived at 486
patients who had had multiple blood tests documenting viral
loads after infection and before they started receiving
antiretroviral treatment.

The three polymorphisms were identified after all the blood
samples of the selected patients were screened for more than
555,000.

Additionally, the researchers discovered many other genetic
variants that may confer protection for patients but whose
effects did not reach statistical significance in the study.
However, some of these polymorphisms could ultimately be shown
to play a major role when future analyses involving more
patients are performed, the researchers said.

Patients involved in the study came from Switzerland, Italy,
United Kingdom, Australia, Spain, and Denmark. The genetic
analysis was performed at Duke and the University Lausanne,
Switzerland. CHAVI is a consortium of scientists from Duke,
Harvard, Oxford, University of North Carolina-Chapel Hill, and
University of Alabama-Birmingham.

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