Immune System Genetics Determine HIV Progression to AIDS

In the first application of a novel statistical technique to the study of disease, researchers found that the genes underlying HIV infected patients' immune systems can predict their risk of progressing to AIDS. Analysis showed that the virus is less likely to progress in patients bearing rare immune system gene variants than in those with more common gene variants.

Thomas Kepler, Ph.D., interim director of Duke University's Center for Bioinformatics and Computational Biology, part of Duke's Institute for Genome Sciences and Policy, said the finding clarifies the interaction between HIV and patients' immune defenses and provides information that may ultimately help doctors tailor treatments to individual patients.

"Specific combinations of alleles [variations of a gene that differ slightly in structure and function] that humans carry appear to protect against HIV," Kepler said. "HIV-infected people who carry particular, rare gene variants have much lower viral loads than other patients do."

The study focused on 996 men, 562 of whom were HIV-positive, enrolled in the Chicago component of the Multicenter AIDS Cohort Study. The researchers genetically screened participants' blood samples for two immune system genes, human leukocyte antigen A and B (HLA-A and HLA-B). HLA molecules orchestrate the response of T cells; the many different HLA alleles have different biological activities that affect the body's response to invasion.

Immune system alleles are notoriously diverse, and Kepler and colleagues were having trouble identifying gene combinations that affect disease outcomes using traditional methods. They devised a novel statistical method, minimum description length (MDL), to divide patients into disease progression groups in a more detailed manner. "The method allowed us to exhaustively go through all possible gene partitions and assign a score to each, while avoiding the pitfalls of traditional methods of analysis," Kepler explained. This research represents the first time MDL has been used to analyze biomedical disease-association data.

The statistical classification of the patients revealed that "greater protection against HIV was afforded by rare immune system alleles," according to Kepler. "That suggests that HIV has adapted to attack the dominant alleles in the population. In other words, the virus goes after the bigger target." Screening patients' immune systems, physicians might ultimately be able to identify patients at the greatest risk for progressing to AIDS and prescribe treatments accordingly.

Study leaders Elizabeth Trachtenberg of Children's Hospital Oakland Research Institute, Calif.; Bette Korber of Los Alamos National Laboratory, N.M.; and Steven Wolinsky of Northwestern University, Ill., were among those who joined Kepler in the collaborative effort. The study, "Advantage of Rare HLA Supertype in HIV Disease Progression," appeared in Nature Medicine (2003;9;(7):928-935).