HLA-C may be Achilles heel of HIV

An international team of researchers has identified three gene variants in 486 people infected with HIV that appear to have helped some of the patients fight off the virus and delay the onset of full-blown AIDS.

The researchers expect the new findings to aid the search for an HIV vaccine that would work by boosting the protective effects of one or more of these genes, and help the body's own immune system overcome an infection. One of the genes looks particularly attractive as a vaccine target.

The study, published online in Science on July 19, was directed by Professor David Goldstein at Duke University and is the first large cooperative study with major findings arising from the Center for HIV/AIDS Vaccine Immunology (CHAVI), a seven-year project funded by the US National Institute of Allergy and Infectious Diseases, part of the US National Institutes of Health.

It took the international genetics team, called EuroCHAVI, pooling their cohorts of carefully selected patients and using the latest in genome-wide screening technology, 18 months to discover the three genes, that together help understand why patients differ in how well they can control the virus that causes AIDS.

The findings represent only first of what investigators said will be a series of future genome-wide studies to pinpoint additional targets for HIV vaccines. In the new analysis, patients with specific polymorphisms in key immune system cells appear to be much better at controlling the proliferation of the virus after infection.

"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 toward new mechanisms of control," Goldstein said.

"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 how some patients are better able to control the virus than others."

"This should ultimately lead to novel targets for vaccines, the primary goal of CHAVI."

Two of the polymorphisms found were in genes controlling the human leukocyte antigen (HLA) system, which plays a major role in the immune system by identifying foreign invaders and "tagging" them for destruction.

Two of the HLA genes, HLA-A and B, are turned off by HIV when it enters the body, which keeps the immune system from recognising the virus as foreign. HLA-C, however, is not thought to be turned off by HIV-1.

The new results suggest that for some individuals at least HLA-C is involved in controlling HIV-1. Since HIV-1 appears unable to shut off HLA-C, unlike A and B, HLA-C may represent an Achilles heel of HIV, according to Goldstein, who said that a vaccine could be designed to elicit an HLA-C mediated response which HIV-1 might be unable to defuse.

"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 to design better treatments and more effective vaccines."