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SNP Studies, Next-Generation Sequencing Target HIV

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As fast-paced as HIV research is, HIV is an even faster-moving virus. Recently, new genomics-based technologies are turning up in the HIV/AIDS field. Ultra-deep pyro-
sequencing may replace the Sanger method as the standard way to detect low-level, and often drug-resistant, strains of HIV that a person might have. Also, genome-wide association studies are highlighting why people react differently to early HIV infection. The goal of both these new approaches is the same as a lot of research in HIV and AIDS: new and better therapeutics.

Robert Shafer, an assistant professor of medicine at Stanford University, studies drug resistance, especially in HIV. By knowing how drug resistance arises in HIV, he hopes this information can improve the drug discovery process and disease surveillance programs, as well as help physicians as they choose a drug regimen for a patient. “We’re very interested in this from a research perspective to understand the population genetics of HIV and other viruses within patients,” Shafer says. “In other words, how does the virus go from wild-type state to a drug-resistant state?”

To go about this, Shafer’s lab has begun to use ultra-deep pyrosequencing, rather than point mutation analysis or standard sequencing, as a faster means of identifying minor HIV variants. When his lab applied this technology to clinical plasma samples, they found an average of two additional drug-resistance mutations than conventional sequencing did. “We did find additional mutations, but because these patients were so heavily treated that wasn’t so much a surprise. We were expecting to,” says Shafer. He hopes that this technology will help characterize the more than 50 positions on HIV’s RNA that are known to mutate in response to therapy and use information about drug resistance to aid others in building better drugs.

Meanwhile, a lab at Duke University studies how people’s inherent genetic variation affects their response to HIV infection. As members of an HIV/AIDS consortium known as CHAVI, their goal “is to try to understand why people differ naturally in how they can control the virus and use that as a guide to figure out [what] the best directions would be for vaccine strategy,” says David Goldstein, a professor of molecular genetics and microbiology. In particular, he focuses on how the body reacts to early infection — when a vaccine would have to act.

Goldstein uses a genome-wide association approach because, he says, “[it] works so well that it would just be silly to do any other kind of genetic discovery right now.” From his initial association study of 500 patients, Goldstein identified three polymorphisms connected to either viral set point or early disease progression. Two loci associated with set point were traced to the human leukocyte antigen region, one of which appears to associate with HLA-C, a gene that was not previously known to play a role in HIV control. The third, dealing with disease progression, was pinned down near two genes, neither of which is an immune gene.

Uncovering the different players that influence how people respond to HIV might lead to pointers for vaccine development. “That may mean that a vaccine that includes an important HLA-C component might strike HIV at a vulnerable point because it can’t act to down-regulate the HLA effect,” Goldstein says. “It gives you a sort of motivation for pursuing that direction.”