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Rare Variants Seen as Next Frontier in Untangling Genetic Differences in HIV Response

CAMBRIDGE, MA (GenomeWeb News) – Researchers are starting to look beyond common variants in an effort to understand the genetics behind individual differences in response to HIV exposure, infection, and treatment.
Speaking at the Genomics of Common Diseases meeting at the Broad Institute in Cambridge this weekend, David Goldstein, director of Duke University’s Center for Population Genomics and Pharmacogenetics, outlined strategies for mining the genome for rare but highly penetrant variants influencing host HIV response. By re-sequencing extreme populations — such as those who appear resistant to HIV infection — Goldstein hopes to uncover rare variants that round out the roster of host genes mediating HIV infection.
A number of studies have demonstrated the dramatic effects that host genetics can have on the course of HIV infection, influencing everything from an individual’s risk of infection to their viral load after infection and treatment response.
In a paper published in Science last August, Goldstein and his team used a genome-wide association study to identify genes influencing viral set point — the amount of viremia in an individual’s blood during the asymptomatic HIV stage — and HIV progression. They pinpointed genetic variants in and around two human leukocyte antigen genes — HLA-B and HLA-C — that explained almost 15 percent of the genetic variation in viral set point. The work also implicated two genes, including an RNA polymerase I subunit gene, in HIV disease progression.
“There really is a marked difference,” Goldstein said, noting that those with no beneficial alleles may require therapy after just two years while those with protective alleles might not need such treatment for eight years or so.
This year, the team published a paper in the September 15th issue of The Journal of Infectious Diseases revealing how an HLA-B allele could help predict hyper-sensitivity to an HIV drug called abacavir.
Similarly, other researchers have identified variants that can help predict HIV treatment response. For instance, in a paper published this spring in Nature Medicine, researchers reported that two genes — CCL3L1 and CCR5 — could be used to predict immune system recovery following highly active antiretroviral therapy.
But although several common variants have been implicated in host HIV response, these variants explain a relatively small amount of the actual individual variation observed in patients. That suggests that the genetic variation influencing individuals’ control of HIV is likely more complex than previously imagined, Goldstein explained.
Having cast their nets for common variants using genome-wide association studies in typical populations, researchers are now beginning to fish in somewhat murkier waters, looking for rare genetic variants with strong effects on HIV response.
Taking a cue from genetic studies of traits, Goldstein noted that re-sequencing individuals with extreme phenotypes may be the most promising strategy for accessing this rare genetic diversity. He proposed using a case control of a thousand or so hemophilia patients who were exposed to HIV in the late 1970s and early 1980s but did not contract HIV.
By genome-wide re-sequencing on these exposed-but-uninfected patients, Goldstein suggested that it should be possible to identify rare genes that explain much more of the variation behind HIV resistance and other host differences. That, in turn, may uncover candidate genes that can be tested in larger studies of more general populations.
Ultimately, Goldstein and others hope to use information about common and rare genetic variants to gain the sorts of biological insights that can be applied clinically, with HIV patients receiving treatments most appropriate to their own genetics.