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Gene Variants That Help Control HIV Infection

Scientists have uncovered genetic clues to explain why some people infected with HIV-1 have lower levels of virus in their blood and ultimately progress to AIDS more slowly.

When a person is first infected with HIV-1, the virus replicates quickly before the immune system steps in to control the infection. The amount of virus in the blood, the "viral load," is checked by the immune system and reaches a steady level called a "set point." At this stage, before symptoms develop, the viral load can vary between people by up to 100,000-fold. In general, the lower the viral load set point the longer the immune system can work properly to fight off other infections and the slower the progression to AIDS.

An international team of researchers led by Dr. David Goldstein of Duke University searched for genetic markers that could explain the huge variation in viral load set point among people infected with HIV. Their work was funded by NIH's National Institute of Allergy and Infectious Diseases (NIAID).

From a pool of 30,000 HIV-positive people, the scientists chose DNA samples from 486 people whose viral load set points had been carefully and accurately measured many times. They applied the DNA samples to gene chips containing more than 555,000 human gene variants that differ by a single nucleotide called single nucleotide polymorphisms (SNPs).

In the online edition of Science on July 19, 2007, the research group reported the discovery of SNPs that can explain nearly 15% of the variation in viral load set point among infected people. The strongest association occurred within a stretch of DNA containing a human retrovirus that was incorporated into the genome a long time ago but no longer produces infectious virus. People with this variant also frequently had a rare immune gene, called HLA-B*5701, near the SNP. The gene codes for a protein expressed on immune cells that is known to play an important role in clearing HIV-infected cells.

A second significant variant associated with lower viral load set point was found in an immune gene called HLA-C. People with this variant appear to make more HLA-C protein than people without the variant. To protect itself from the immune system, HIV can inhibit the expression of two related immune proteins that recognize virus-infected cells and help eliminate them from the body. However, scientists believe that HIV cannot similarly reduce HLA-C levels.

"If scientists could design a vaccine to enhance HLA-C-mediated immune responses," Dr. Goldstein says, "they might be able to hit HIV at a vulnerable point."

The research team also found variants in a third area that were linked to disease progression. This first genome-wide picture of host responses to HIV provides new avenues for the development of vaccines and improved HIV therapies.