Genetic Analysis Offers Insights Into AIDS Resistance

THURSDAY July 19, 2007 -- Variations in three genes play a critical role in how different people infected with HIV respond during the early stages of their infection.

This finding, detailed in the July 20 issue of Science, could help scientists find vaccines as well as new treatment targets for people infected with the AIDS-causing virus.

"There are new mechanisms of control of HIV1 that are implicated by these findings," said study senior author David Goldstein, a professor of molecular genetics and microbiology at Duke University and director of the school's Center for Population Genomics and Pharmacogenetics. "We don't yet know how to capitalize on those new mechanisms to develop new treatments, but it establishes directions for exploring new treatment options."

The study results are the first to emerge from the Center for HIV/AIDS Vaccine Immunology (CHAVI), a seven-year project funded by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) with a goal of understanding the genetic influences on early responses to HIV infection. Many more studies are planned.

"We're really only just getting started," Goldstein said.

"It is a very important study," said NIAID Director Dr. Anthony Fauci. "It's significant for a couple of reasons. First of all, it used a technique that is going to be increasingly used in the genetics of medicine and that is to do a genome-wide association study to try and identify genes or modifications of genes which we call polymorphisms that are associated with certain expression of disease."

People infected with HIV have widely varying responses to their infection, with some falling sick quickly and others successfully fighting off full-blown AIDS for years or even decades.

One measurable difference is the level of circulating virus in the blood during the "stable" period after a person is infected but before he or she develops symptoms. This "viral load" is generally an indication of how well the person's immune system is fighting off the infection.

The new study searched for genetic differences that might explain variations in viral loads.

"One of the big questions in HIV is what are the determinants of the great variability in individuals being able to handle the virus. That's a big, big open question," Fauci said. "One of the ways to address that is to say look, there are some people whose viral set point, the level at which the body holds the virus in the absence of therapy, that varies enormously from person to person. We have no idea why that's the case. This study came up with three gene polymorphisms which appear to be associated very strongly with the ability to set the viral load. The combination of those explains about 15 percent of the variation in viral load among patients."

"The approach that we've taken is to use these natural differences among individuals in how well they can control the virus after infection as a pointer to new ways to act against the virus," Goldstein said. "That variation is huge. Some can push viral levels so low they will never progress to AIDS, whereas others can hardly contain it."

It took the international team of geneticists 18 months to identify the three crucial genes. In the end, they identified 486 appropriate patients from a possible universe of 30,000 people worldwide, and did genome-wide scanning on these patients. The study participants could not be undergoing treatment (as this would affect viral load levels), they had to know when they became infected, and there had to be high-quality laboratory estimates of their viral load.

This was the first time a genome-wide approach has been used for an infectious disease, the researchers said.

Two of the gene variants -- or polymorphisms -- were found in genes controlling the human leukocyte antigen (HLA) system, which helps identify foreign invaders and tags them for destruction. These genes, HLA-A and HLA-B, are switched off by HIV when it enters the body so the immune system is no longer able to recognize the virus as foreign.

Research published in the May 13 issue of Nature Genetics also implicated the HLA-B gene. That study found that HLA-B, in combination with another gene, KIR3DL1, might confer some protection against AIDS progression.

But HIV doesn't seem to be able to shut off HLA-C, the third gene variant identified by the researchers behind the new study. "This had not been a focus of attention in the past because it was not known that it is important in the control of HIV," Goldstein said. "We've now implicated this part of the immune response as being important so it now becomes a focus."

"It might be that this gene represents a vulnerable point for HIV," he added. "As far as we know, HIV can't act against it."

The three gene variants identified in the study explain 15 percent of the variability in how well people contain their viral load. "In genetic terms, that's a lot," Goldstein said. "These are very important genetic effects."

The next CHAVI study will look at what factors might protect people from becoming infected with HIV in the first place.

More information

Visit CHAVI for more on cutting-edge HIV/AIDS research.

Posted: July 2007


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