HIV genetics by the genome

A new whole-genome association study has found more genetic variants protective against HIV. The course of HIV infection is variable, even in the absence of medication, and it has been known for some time that some of the variation in disease progress is attributable to genetic variation among people. One gene variant (CCR5Δ32) is strongly protective against HIV-1; this is because the virus exploits the CCR5 chemokine receptor to infect T cells, and homozygotes for the Δ32 allele do not have this vulnerability.

The new research looked through the entire genome to find single nucleotide polymorphisms (SNPs) associated with variant disease phenotypes:

Understanding why some people establish and maintain effective control of HIV-1 and others do is a priority in the effort to develop new treatments for HIV/AIDS. Using a whole-genome association strategy we identified polymorphisms that explain nearly 15% of the variation among individuals in viral load during the asymptomatic set point period of infection. One of these is found within an endogenous retroviral element and is associated with major histocompatibility allele HLA-B*5701, while a second is located near the HLA-C gene. An additional analysis of the time to HIV disease progression implicated a third locus encoding a RNA polymerase subunit. These findings emphasize the importance of studying human genetic variation as a guide to combating infectious agents.

From a very large study population of infected patients, the authors were able to identify a subset for whom recurrent measurements of viral load and other essential data were available. This allowed them to find genes that associate with the temporal progression of the disease, not just its presence or absence. An article on ScienceNOW by Jon Cohen describes the setup:

The team studied 486 patients infected with HIV who had not received treatment and had known dates of infection and accurate set points. Then they checked blood samples against half a million known variations in DNA sequences, or single-nucleotide polymorphisms, which recently were identified by the International HapMap Project that looked for differences in the genomes of people from many populations. "We've approached this as a straight, quantitative genetic problem," explains David Goldstein, a geneticist at Duke University in Durham, North Carolina, who led the study. The researchers say this is the first study to ever do such a genome-wide association analysis for an infectious disease.

The study identifies a number of other candidates besides the three significant ones that receive most of the discussion. It's tricky to test for significance in genome-wide surveys because the genome is so large and there are potentially many genes with small effects on disease phenotype. Still, genes with small effect (unless rare and highly protective) are not particularly good candidates for therapeutic treatments, so the major ones are the main story.

References:

Fellay J and 26 others. A whole-genome association study of major determinants for host control of HIV-1. Science (online early) doi:10.1126/science.1143767