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They don’t develop clinical disease, are less likely to transmit HIV to others, and the number of key infection fighting cells in their immune system remains stable.

How does this small minority of so-called HIV “controllers”—about one in 300 people infected with HIV—keep the virus in check? An international team of investigators may have found the genetic basis for the answer.

“People who are controlling HIV are able to prime their own immune system, to get it to target the virus very effectively. And that’s what this paper demonstrates nicely,” says Joseph Eron, study co-author and professor of medicine at the University of North Carolina at Chapel Hill.

Researchers found differences in five amino acids in a protein called HLA-B are associated with whether or not HIV-infected individuals can control viral levels with their immune system only. Findings are reported in the journal Science.

The cellular immune system relies largely on HLA-B to recognize and destroy infected cells. “In other words, the immune system’s success in controlling HIV is based on how well it can take parts of the virus and carry them to the membrane of the infected cell where they can be displayed and marked for destruction by ‘killer T cells,’” Eron explains.

“Of three billion nucleotides in the human genome, just a handful make the difference between those who can stay healthy in spite of HIV infection and those who, without treatment, will develop AIDS,” says co-senior author Bruce Walker, director of the Ragon Institute of Massachusetts General Hospital.

The research involved a multi-ethnic genome-wide association study (GWAS) of some 1,000 controllers and 2,600 individuals whose HIV infection had progressed. Blood samples were tested for variants throughout the genome, which identified about 300 sites that were statistically associated with immune control of HIV.

All of the sites, or single nucleotide polymorphisms (SNPs), were found only within regions of chromosome 6 that code for HLA proteins. And direct testing of those SNPs linked five amino acids within the HLA-B protein to differences in viral control.

“To do studies like this, it really does take a village,” Eron says, pointing out that the work required the participation of the hundreds of HIV controllers, among them UNC patients, and many having traveled to Boston for testing.

“The needle in the haystack are the controllers … especially those whose levels of HIV are below the limit of detection. We know they’re infected because they have a positive antibody response and occasionally they’ll have a little bit of virus in their blood plasma.”

Researchers say the new findings could form the basis for additional studies that might eventually lead to a vaccine against HIV.

The work, co-led by researchers at Harvard University, MIT, and the Ragon Institute, was supported in part by grants from the Bill and Melinda Gates Foundation and the National Institutes of Health. More than 300 researchers collaborated on the study, including those from Vanderbilt University, Stanford University, Cornell University, UC San Diego, University of Pittsburgh, McGill University, University of Iowa, Johns Hopkins University, Brown University, NYU, University of Washington in St. Louis, Yale University, and Northwestern University.

More news from UNC: http://uncnews.unc.edu/