Clearer picture of host responses to HIV virus

The first genome-wide association study of an infectious disease, conducted by an international group of researchers through the Center for HIV/AIDS Vaccine Immunology (CHAVI), has yielded a new understanding of why some people can suppress virus levels following HIV infection.

"The clearer picture of host responses to the virus achieved through this examination of genomes could lead to improved HIV therapies and provides new targets for vaccine developers," says Elias A. Zerhouni, M.D., director of the National Institutes of Health (NIH). CHAVI, which is led by Barton Haynes, M.D., of Duke University, Durham, N.C., was established in 2005 by the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH.

CHAVI's host genetics team, led by David Goldstein, Ph.D., also of Duke University, included scientists from several European countries and Australia who formed a consortium, EuroCHAVI, to perform this study. The investigators identified three gene variants, two of which are linked to an infected person's ability to control HIV viral load and a third that is implicated in disease progression to AIDS. The research is being published by Science on the Science Express Web site on Thursday, July 19.

"CHAVI is designed to foster collaborative research to overcome roadblocks that have impeded HIV vaccine development," says NIAID Director Anthony S. Fauci, M.D. "The insights into genetic factors influencing host control of HIV revealed by this work exemplify the power of such collective investigations."

Genome-wide association studies aim to identify genetic variations among people that can be tied to variations in disease susceptibility. Recent genome-wide association studies have found genetic markers linked to increased risk of such ailments as diabetes, cancer and heart disease. The CHAVI investigators are the first to apply genome-wide association techniques to an infectious disease.

"People vary greatly in their vulnerability to HIV infection," notes Dr. Haynes. "In particular, there are striking and largely unexplained differences between individuals in the degree to which they are able to hold viral levels to a low set point in the period soon after infection." If scientists could pinpoint the gene variants that help some people control HIV infection--or avoid it altogether--they might be able to rationally design therapies or vaccines to mimic these naturally occurring genetic advantages, he notes.

In 2006, CHAVI researchers launched an effort to pool genetic data from HIV-positive individuals who had enrolled in nine studies based throughout Europe and in Australia. Together, these studies contained information on more than 30,000 individuals. From this pooled cohort, the CHAVI scientists ultimately chose 486 DNA samples--representing the genomes of 486 HIV-positive people whose viral load set points had been carefully and accurately measured at multiple time points--for the genome-wide association study.

The scientists applied the genome samples to gene chips dotted with more than 550,000 human gene variants, called single nucleotide polymorphisms or SNPs. The sweep of genomes found three SNPs that were strongly associated with either viral load set point or disease progression. The two variants associated with viral load can explain 15 percent of the total variation among all infected individuals, the scientists estimate.

One of the identified variants is near a human immune gene called HLA-C, and may provide a new route for HIV vaccine developers to explore, says Dr. Goldstein. People with the identified variant are thought to make more of the gene's product than people who lack this presumably protective genetic variant. A consequence of this extra production of HLA-C protein, researchers hypothesize, is that the immune system is better able successfully identify and remove HIV-infected cells, thus keeping viral load set points low for long periods.

HIV has many ways to defend itself from immune system efforts to eliminate it. One defense is the ability of an HIV gene, nef, to decrease the production of two related immune system proteins, HLA-A and HLA-B. Nef, scientists believe, is not able to similarly hamper the expression of HLA-C. If scientists could design a vaccine to enhance HLA-C-mediated immune responses, they might be able to hit HIV at a vulnerable point, says Dr. Goldstein. Although HLA-C had previously been suspected of contributing to HIV control, this genome-wide study is the first to confirm the association, he adds.

The CHAVI investigators are currently building on these studies of polymorphisms to pinpoint the specific human gene variants that influence HIV replication.

"We applaud the CHAVI investigators for the highly collaborative nature of this work. It demonstrates that answers to important questions, requiring analysis of large amounts of clinical specimens, can be obtained quickly," says Peggy Johnston, Ph.D., director of NIAID's Vaccine Research Program.