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.
Copyright - The National Institute of Allergy and Infectious Diseases
The Influence of CCL3L1 Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility
Enrique Gonzalez, Hemant Kulkarni, Hector Bolivar, Andrea Mangano, Racquel Sanchez, Gabriel Catano, Robert J. Nibbs, Barry I. Freedman, Marlon P. Quinones, Michael J. Bamshad, Krishna K. Murthy, Brad H. Rovin, William Bradley, Robert A. Clark, Stephanie A. Anderson, Robert J. O'Connell, Brian K. Agan, Seema S. Ahuja, Rosa Bologna, Luisa Sen, Matthew J. Dolan, and Sunil K. Ahuja
Published online 6 January 2005 [DOI: 10.1126/science.1101160] (in Science Express Research Articles)
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