Scientists Discover Key Genetic Factor in Determining HIV/AIDS Risk
People with more copies of a gene that helps to fight HIV are less
likely to become infected with the virus or to develop AIDS than
those of the same geographical ancestry, such as European Americans,
who have fewer copies of the gene, according to a study funded by
the National Institute of Allergy and Infectious Diseases (NIAID),
part of the National Institutes of Health (NIH). The findings help
to explain why some people are more prone to HIV/AIDS than others.
Scientists believe that this discovery could lead to a screening
test that identifies people who have a higher or lower susceptibility
to HIV/AIDS, potentially enabling clinicians to adapt treatment
regimens, vaccine trials and other studies accordingly. The research
appears Jan. 6 in Science Express, an online publication
of the journal Science.
“Individual risk of acquiring HIV and experiencing rapid
disease progression is not uniform within populations,” says
Anthony S. Fauci, M.D., director of NIAID. “This important
study identifies genetic factors of particular groups that either
mitigate or enhance one’s susceptibility to infection and
disease onset. In a broader sense, it also suggests how the immune
systems of individuals with different geographical ancestries might
have evolved in response to microbial stresses and how these differences
in the immune system might result in medical approaches to thwart
HIV/AIDS or other infections that vary among groups.”
The study focused on the gene that encodes CCL3L1, a potent HIV-blocking
protein that interacts with CCR5 — a major receptor protein
that HIV uses as a doorway to enter and infect cells. The senior
authors are Sunil K. Ahuja, M.D., of the University of Texas Health
Science Center and the Veterans Administration Center for AIDS
and
HIV-1 Infection in San Antonio, and Matthew J. Dolan, M.D., of
the U.S. Air Force’s Wilford Hall Medical Center and Brooks
City-Base in San Antonio.
The researchers analyzed blood samples from more than 4,300 HIV-positive
and -negative people of different ancestral origins to determine the
average number of CCL3L1 gene copies in each group. They found that,
for example, HIV-negative African-American adults had an average
of four CCL3L1 copies, while HIV-negative European- and Hispanic-American
adults averaged two and three copies, respectively.
This does not mean that European Americans are more prone to HIV/AIDS
than other populations. Rather, using the average CCL3L1 gene copy
number as a reference point for each group, the authors found that
individuals with fewer CCL3L1 copies than their population’s
average were more susceptible to HIV infection and rapid progression
to AIDS. People with greater-than-average CCL3L1 gene copies, in
contrast, were less prone to infection by HIV or to rapid progression
to AIDS.
Depending on the study population, each additional CCL3L1 copy lowered
the risk of acquiring HIV by between 4.5 and 10.5 percent. Additionally,
below-average CCL3L1 copy numbers were associated with a 39 to 260
percent higher risk of rapid progression to AIDS.
To further test the impact of CCL3L1 copies on HIV/AIDS risk, the
researchers then studied variations in the CCR5 gene that they had
previously linked to varying rates of AIDS progression. They found
that individuals who possessed a low CCL3L1 copy number along with
disease-accelerating CCR5 variants had an even higher risk of HIV
acquisition and rate of progression to AIDS.
“This work adds significantly to our understanding of the
central role that molecules that interact with the CCR5 co-receptor
play in influencing susceptibility to HIV/AIDS,” says Carl
W. Dieffenbach, Ph.D., who oversees basic research at NIAID’s
Division of AIDS. “In addition, by examining the duplication
of a specific gene, this study further emphasizes the significance
of defining all existing types of genetic variation and the impact
that these variations may have on human susceptibility to infectious
diseases.”
The study is the result of collaboration between NIAID-supported
researchers and investigators from the U.S. Military’s Tri-Service
AIDS Clinical Consortium. “This partnership highlights the
importance of inter- and multi-disciplinary research teams in clinical
genomic research, a theme heavily emphasized in the NIH Roadmap,”
says NIAID’s Dr. Dieffenbach.
The research also received support from the National Institute of
Mental Health, another NIH component; the Veterans Administration
Center for AIDS and HIV-1 Infection; the Elizabeth Glaser Pediatric
AIDS Foundation; and the Burroughs Wellcome Fund.
NIAID is a component of the National Institutes of Health, an
agency of the U.S. Department of Health and Human Services. 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 transplantation
and immune-related illnesses, including autoimmune disorders, 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.
Reference: E Gonzalez et al. The influence of CCL3L1 gene-containing
segmental duplications on HIV-1/AIDS susceptibility. Science
DOI: 10.1126/science.1101160.
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