Pace of AIDS progression not dependent on viral load alone (10/25/2007)

Armed with genetic information from more than 3,500 HIV-1-infected subjects and healthy individuals, a large multidisciplinary team from The University of Texas Health Science Center at San Antonio; the U.S. military; Massachusetts General Hospital/Harvard; The University of California, San Francisco; Australia; Colombia; and Argentina reported this week that two genes influence AIDS progression rates by affecting not just the extent of viral replication but also the strength of the body's immune response.

The finding challenges the quarter-century-old emphasis on viral load as the chief contributor to progression from initial HIV-1 infection to AIDS, and places the spotlight on the importance of the body's immune response in combating HIV-AIDS. The results of the study, released online Oct. 21 by the prestigious journal Nature Immunology, emphasize that it is not the viral burden itself but instead the interaction between the virus and host factors that switches "what might have been an otherwise benign infection to a lethal one," the scientists wrote.

"The extent of HIV-1 replication during initial stages of infection accounts for only 9 percent of variability of progression to AIDS, and what we show is that genetic variations in the primary HIV-1 co-receptor, called CCR5, and an immune-response gene, CCL3L1, contribute nearly as much to the extent of inter-individual variability in AIDS progression rates as does HIV-1 viral load," said the study's co-senior author, Sunil K. Ahuja, M.D., professor of medicine, microbiology, immunology and biochemistry at The University of Texas Health Science Center at San Antonio. He is also director of the Veterans Administration Research Center for AIDS and HIV-1 Infection in the South Texas Veterans Health Care System.

The CCR5 co-receptor is a second portal on the cell surface that facilitates HIV-1 entry along with the CD4 cell receptor.

"These findings show that genetic variation in CCR5 and CCL3L1 together might dictate the extent of this harmful switch, because even after accounting for the detrimental effects of a high viral burden, these genetic factors influence the pace of HIV-1 disease progression," said Hemant Kulkarni, M.D., co-first author of the paper and assistant professor of medicine at the Health Science Center.

The other co-senior and co-first author, Matthew Dolan, M.D., from San Antonio Military Medical Center and the Infectious Disease Clinical Research Program of the Uniformed Services University of Health Sciences in Bethesda, Md., said the finding could have major implications for the care of HIV-positive subjects "because it brings us closer to the possibility of using genetic information along with laboratory tests such as the CD4 count and viral load to assess AIDS risk."

Dr. Dolan indicated that "these studies also point to the importance of possible use of genetic information in evaluation of vaccines." Dr. Ahuja added: "Clinical trials of potential vaccines certainly need to look at other endpoints than reduction of viral load, and may need to account for the disease-modulating effects of host genotype."

Co-authors from the Health Science Center and the VA HIV-1/AIDS center also include Drs. Jose Camargo, Weijing He, Manju Mamtani, Robert Clark and Seema Ahuja. This work was supported by multiple organizations including the National Institutes of Health and the VA.

"Every piece of science is an incremental step of progress," said Douglas D. Richman, M.D., director of the Center for AIDS Research at The University of California, San Diego. "This is a really nice piece of work that is typical of Dr. Ahuja - thorough, scholarly, comprehensive, with new insights of the contribution of various host genes to HIV transmission and disease progression."

Note: This story has been adapted from a news release issued by The University of Texas Health Science Center

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