Geneticists have uncovered intriguing new clues about why some people battle HIV more effectively than others. The findings, published online 19 July in Science, may ultimately reveal why these people tend to develop AIDS more slowly.
The body's first response to HIV strongly influences how fast the virus will destroy the immune system. Shortly after infection, HIV levels skyrocket, but then the immune system and other antiviral factors produced by cells drive down the amount of virus in the blood--the so-called viral load--and establish a "set point." The lower the set point, the longer the immune system can function effectively. These set points vary widely, and researchers with the U.S.-based Center for HIV-AIDS Immunology and European collaborators hunted for a genetic explanation.
The team studied 486 patients infected with HIV who had not received treatment and had known dates of infection and accurate set points. Then they checked blood samples against half a million known variations in DNA sequences, or single-nucleotide polymorphisms, which recently were identified by the International HapMap Project that looked for differences in the genomes of people from many populations. "We've approached this as a straight, quantitative genetic problem," explains David Goldstein, a geneticist at Duke University in Durham, North Carolina, who led the study. The researchers say this is the first study to ever do such a genome-wide association analysis for an infectious disease.
Goldstein and co-workers unearthed two polymorphisms in genes that explain 15% of the variation seen in viral set points. The effects of the polymorphisms were independent of one another, and both correlated with lowered set points. The more powerful one occurred within a stretch of DNA, or locus, that contains the HCP5 gene, which codes for a human endogenous retrovirus--a genetic fossil of a virus that wove itself into human chromosomes long ago but no longer produces infectious progeny.
Intriguingly, the researchers found that the people who had the HCP5 polymorphism often had a rare gene that can powerfully thwart HIV. That gene, HLA-B*5701, codes for a protein on immune cells that plays a central role in clearing the body of HIV-infected cells. "This research is very important, but it remains to be clarified what the role of these two loci are," says Mark Connors, an immunologist at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, whose lab first reported that HIV-infected people who remain unharmed by the virus for many years often have the HLA-B*5701 allele.
The second implicated polymorphism is in the HLA-C gene, which plays a similar role to HLA-B in mounting an effective immune response. The researchers do not know the mechanisms through which these polymorphisms lower viral set points but suggest that if they can be unraveled, the findings may lead to new targets for anti-HIV drugs and new vaccine strategies.
AIDS researcher Steven Wolinsky of Northwestern University Medical School in Chicago, Illinois, cautions that this study largely focused on Caucasians: "I would have more confidence in the data if they could replicate the results in the context of a different genetic background." Wolinsky notes that similar findings in the past have turned out to appear in some cohorts but not others: "It's an interesting association, but it really needs to be validated."
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