USIS Washington File - July 26, 2007
Cheryl Pellerin, USINFO Staff Writer

The researchers, led by David Goldstein, professor of molecular genetics and microbiology at Duke University in North Carolina, expect their findings to help in the search for AIDS treatments, and an HIV vaccine that would work by boosting the effects of apparently protective genes.

"People really vary in their vulnerability to HIV," said Goldstein, also director of the Duke Institute for Genome Sciences and Policy, during a July 23 USINFO interview.

"Some people, despite repeated, high degrees of exposure, will not become infected," he added. "And even for those who do become infected, their immune systems are able to control the virus just fine. So far as we know, perhaps as many as 10 percent of people who do become infected will not become sick."

But most people exposed to HIV progress to AIDS. More than 64.9 million people have been infected with HIV since the pandemic began in the 1980s, according to the U.S. Agency for International Development, and the Joint United Nations Programme on HIV/AIDS estimates that 39.5 million people worldwide were living with the disease in 2006.

NATURAL RESISTANCE

The work, published July 19 in the online issue of Science, is the first large cooperative study with major findings arising from the Center for HIV/AIDS Vaccine Immunology (CHAVI), funded by the National Institute of Allergy and Infectious Diseases, part of the U.S. National Institutes of Health.

CHAVI is a consortium of researchers from Duke University, the University of North Carolina-Chapel Hill, the University of Alabama-Birmingham, Harvard Medical School in Massachusetts and Oxford University in the United Kingdom.

"Within CHAVI," Goldstein said, "we established a consortium of investigators called EuroCHAVI who worked together to establish a group of subjects for analysis."

The investigators -- from Switzerland, Italy, the United Kingdom, Australia, Spain and Denmark -- looked through the records of 30,000 patients to find 486 patients with specific characteristics.

"We had to know when they became infected, within a two-year window," Goldstein said, "and we had to have a laboratory estimate of their viral load during the time that they were not treated." Viral load is the number of virus copies or particles in a milliliter of a patient's blood.

When a person is infected by HIV, viral load rises to a high level before the immune system pushes it down to a stable level, called a set point. Some people can push the virus to undetectable levels; those who cannot control it progress rapidly to AIDS.

To find out why some people can push the virus to such low levels, Goldstein and his team focused on the viral load set point. What, they asked, controls how much virus is present at the set point?

CHIPS AND SNIPS

To answer that question for each of the 486 study subjects, the scientists used a genetic tool -- a microassay on a credit-card-sized wafer or "chip" that simultaneously tests 550,000 of a genome's 3 billion sites -- to see which of the sites, called single nucleotide polymorphisms, or SNPs (pronounced "snips"), might influence the trait of viral load.

The researchers extracted DNA from the subjects, prepared it for the assay and ran each sample over a chip. The 550,000 SNPs represent the 10 million or so SNPs on the genome that vary from one person to the next.

Over 18 months, the sweep of genomes found three SNPs that were strongly associated with either viral load set point or disease progression. The SNP most relevant to a potential vaccine is near a human immune gene called HLA-C. People with this variant are thought to make more of the gene's potentially protective product than people who do not have it.

The HLA genes are involved in presenting foreign bits of protein on the surface of cells in the body to let the immune system know that the cell is infected and should be destroyed.

Nobody knew the identified gene "was able to act in this way to flag HIV-infected cells for destruction," Goldstein said. And HIV does not interfere with the gene, "which could mean that a vaccine strategy working through this mechanism might be a vulnerable point for HIV."

"We don't know whether it's going to work or not," Goldstein added, "but it's a possibility that would not have been a focus before these results."

Next steps include expanding the genetic analysis to larger samples to find other genetic determinants, examining resistance to infection, and doing functional work to better understand how genetic differences have their effects.

More information about the Global Enterprise and CHAVI can be found on the organizations' Web sites.

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