Number of copies of immune-response gene linked to HIV/AIDS susceptibility

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San Antonio (Jan. 7, 2005) – The likelihood of acquiring HIV and, once infected, of progressing to full-blown AIDS is much greater in people who have a below-average number of copies of a particular immune-response gene, according to a study conducted by The University of Texas Health Science Center at San Antonio, Wilford Hall Medical Center and other sites.

Funding was provided by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health (NIH); the Veterans Administration Center for AIDS and HIV-1 Infection in San Antonio; and other agencies.

The article was released Jan. 6 in Science Express, a publication of the journal Science.

Unlike most genetic studies that focus on single nucleotide polymorphisms (minute variations that occur in the genetic blueprint and are used to track inheritance in families), the study authors focused on an unusual polymorphism, namely variable copy numbers of the gene encoding CCL3L1. “We selected CCL3L1 because it interacts with a receptor called CCR5, which is the main portal for entry of HIV into cells,” says the study’s senior co-author, Sunil K. Ahuja, M.D., professor of medicine and microbiology and immunology at the Health Science Center and director of the VA Center for AIDS and HIV-1 Infection.

“CCL3L1 is a potent anti-HIV infection-fighting molecule,” Dr. Ahuja added. “Thus, we tested the possibility that individuals possessing a low number of copies of the CCL3L1 gene might be more susceptible to acquiring HIV and progressing to AIDS.”

HIV-positive subjects indeed were found to have substantially fewer copies of CCL3L1 than HIV-negative subjects. Depending on the study population, each CCL3L1 copy decreased the risk of HIV infection by 4.5 percent to 10.5 percent. The study used multiple complementary analytical approaches to arrive at this conclusion. Lower CCL3L1 count also was associated with poorer clinical outcome for those infected with HIV.

The researchers examined blood samples from 4,308 HIV-positive and -negative individuals of different geographical ancestries (African and European descent). This was accomplished through a multi-population patient cohort at Wilford Hall Medical Center, with support from the Henry M. Jackson Foundation, the U.S. Military HIV Program at the Walter Reed Army Institute of Research and the Tri-Service AIDS Clinical Consortium.

The study revealed differences among individuals and ethnic/racial groups in the number of CCL3L1 copies. “It is important to note that an individual’s HIV/AIDS susceptibility did not hinge on absolute copy number, according to our study, but on whether the individual had fewer or more CCL3L1 genes than the average number in his particular ethnic/racial group,” says senior co-author Matthew J. Dolan, M.D., of Brooks City-Base in San Antonio.

To further test the CCL3L1 hypothesis, the authors also studied variations in the CCR5 gene that they previously had linked to variable rates of AIDS progression. Using multiple analytical approaches, they showed that individuals who possess both low CCL3L1 copy number and disease-accelerating CCR5 variants have a markedly enhanced risk of HIV acquisition and rate of progression to AIDS.

Specifically, they found this dual genetic marker for CCL3L1 and CCR5 was associated with a more than threefold greater risk of rapid progression to eight of 12 AIDS-defining illnesses such as Kaposi sarcoma and cryptococcosis. This was in comparison to individuals who possessed the more “protective” genotype composed of a high number of CCL3L1 gene copies along with CCR5 variants that are associated with a more benign disease course.

“This new study further paints the picture of a ‘permissive genetic background’ that, for some individuals, means they are at much greater risk to acquire HIV infection and, once infected, to progress to full-blown AIDS,” Dr. Ahuja says. “CCL3L1 also may have a stronger effect than CCR5 on HIV acquisition and progression at the population level.”

The findings could lead to development of new therapies, he says. In addition, researchers equipped with this new knowledge may be able to develop a vaccine to protect HIV-negative individuals from ever becoming infected, or use this information for designing better vaccine trials.

Study co-authors are from The University of Texas Health Science Center at San Antonio, Wilford Hall Medical Center, Brooks City-Base and the South Texas Veterans Health Care System’s VA Research Center for AIDS and HIV-1 Infection, all in San Antonio; J.P. Garrahan Children’s Hospital in Buenos Aires, Argentina; the Cancer Research UK Beatson Laboratories in Glasgow, Scotland; the Wake Forest University School of Medicine; the University of Utah; the Southwest Foundation for Biomedical Research, San Antonio; Ohio State University; the Henry M. Jackson Foundation; and the Tri-Service AIDS Clinical Consortium.

The study also received funding from the National Institute of Mental Health, another NIH component.



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