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Paradox for RANTES polymorphism
SNP is associated with increased risk for HIV infection and delayed progression
Edward R. Winstead

A study involving a gene implicated in AIDS has yielded a puzzling result: A single nucleotide polymorphism, or SNP, was associated with an increased risk for HIV infection and a delayed progression toward AIDS following infection.

Researchers have identified five or six SNPs that may influence susceptibility to HIV disease.

The SNP occurs in the regulatory region of the RANTES gene. RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted) belongs to a class of molecules known as beta-chemokines. The SNP increases the expression of the RANTES gene, which produces molecules that are also called RANTES. These molecules bind to the same targets used by the HIV virus to enter cells. Thus, the competition for targets impedes the spread of the virus.

"By blocking the access of HIV to the binding sites, RANTES can act like a chemical condom," says Philip M. Murphy, of the US National Institute of Allergy and Infectious Diseases (NIAID). Murphy's group collaborated on the study with investigators at the University of Manchester Medical School, in the United Kingdom.

Individuals with the HIV virus progress from initial infection to onset of AIDS at very different rates, and researchers have been trying to identify genetic factors that protect against or increase susceptibility to disease. The new findings support the hypothesis that a person's genome plays a role in HIV disease, just as it does in other diseases.

Last year, another team of researchers reported an association between the SNP and delayed progression of HIV disease in a population of infected hemophiliacs. In the current study, individuals with the SNP who became infected with HIV took about 40 percent longer to develop AIDS than did those without the SNP. The mode of viral transmission for most of the subjects was sexual contact. The researchers investigated variants of the RANTES gene in HIV-positive and HIV-resistant individuals who participate in the Multicenter AIDS Cohort Study.

The researchers have a plausible explanation for the delayed disease progression. They already suspected that RANTES is a kind of endogenous HIV suppressor, and having more RANTES is consistent with a slowing of disease progression. But this does not explain why the SNP might the increase risk for infection.

"We don't really understand the mechanism behind the increased risk for infection," says Murphy, a senior investigator in the Laboratory of Host Defenses at NIAID. "We've associated a SNP with a particular outcome, and the reasons are plausible but speculative."

The 1999 RANTES study involving HIV-infected hemophiliacs in Japan did not address the question of risk for infection. Nonetheless, the new findings do fit a pattern. Since the mid-1990s, AIDS researchers have identified five or six SNPs that may increase or decrease susceptibility to HIV disease. The strength of the associations varies depending on the SNP, but several studies have linked a mutation in a gene called CCR5 to better disease outcomes.

"When you put all of these dots on a canvas," says Murphy, "you get a picture of how people with different genetic backgrounds could get very different disease outcomes over the course of 20 years."

AIDS researchers emphasize that no genetic factors are known to protect against infection, so measures to prevent transmission of the virus are as important as ever. The association studies have no immediate implications for infected individuals. The hope is that understanding disease susceptibility and responsiveness to drugs will facilitate more personalized treatments down the road.

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McDermott, D.H. et al. Chemokine promoter polymorphism affects risk of both HIV infection and disease progression in Multicenter AIDS Cohort Study. AIDS 14, 2671-2678 (2000).

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