July 19, 2007
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 Host Genetics team led by Dr. David Goldstein at Duke University included scientists from several European countries and Australia that 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 towards frank AIDS (measured through the depletion of a specific population of immune cells). The results from this 18 month study were published on July 19, 2007 in Science Express on the Science website. The study is the first large cooperative study with major findings arising from the Center for HIV/AIDS Vaccine Immunology (CHAVI).
“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.”
“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.
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 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.
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 before they started receiving antiretroviral treatment.
When someone becomes infected with HIV, the amount of virus in the blood spikes as the virus multiplies. After this peak, the amount of virus in the blood, known as the viral load, gradually decreases and then levels off, a period during which patients do not exhibit symptoms of their disease. The viral load during this leveling out is an indication of how well the patients’ own immune system is battling the virus, and this is the point in the infection’s natural history that the researchers studied.
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 HIV-positive genomes found three SNPs that were strongly associated with either viral load set point or duration of time until full-blown AIDS develops. The three polymorphisms were identified after all the blood samples were screened for more than 555,000 polymorphisms and battery of statistical tests performed. The two variants associated with viral load can explain 15 percent of the total variation among all infected individuals, the scientists report. All previous genetic studies of host genetic control of viral load set point together explained only 5 percent of the total variation.
These results not only approximately double our understanding of the factors that influence variation amongst individuals in how they control HIV-1, but also point towards new mechanisms of control” said David Goldstein, Ph.D., director of the Center for Population Genomics and Pharmacogenetics at Duke’s Institute for Genome Sciences & Policy. Goldstein is the senior author of the paper.
“As we expand the number of patients in future studies conducted by CHAVI researchers, we aim to discover even more polymorphisms that could provide additional clues of how some patients are better able to control the virus than others,” Goldstein. “This should ultimately lead to novel targets for vaccines, the primary goal of CHAVI.”
One of the identified variants, in near a human immune gene called HLA-C, 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 to 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.
“This study was the first time a genome-wide approach has been used for an infectious disease,” Goldstein said. “Past studies have looked at individual candidate genes. Since different people respond differently to infections, a better understanding of how immune system genes control responses to infections should help us design better treatments and more effective vaccines.”
“CHAVI was designed to do big science, and the results of this analysis represent just the first of what should be many advances,” Haynes said. “The technology used and collaborative efforts involved were remarkable – together as a group we were able to do something that none of us individually could accomplish. The results of this and future CHAVI studies should help individual laboratories across the world perform research to better understand the virus.”