HIV infection is less likely to progress in individuals with rare immune system gene variations than in those with common variations, suggesting that HIV has evolved to exploit the most common human HLA patterns, according to a new study published this week in Nature Medicine.
Although the findings have no immediate application in HIV therapy, they may eventually allow clinicians to identify which patients will experience faster disease progression.
"Specific combinations of alleles that humans carry appear to protect against HIV," said Thomas Kepler PhD of Duke University, North Carolina, who developed the techniques used to investigate the contribution of various genes in the human immune system to HIV disease progression. "HIV-infected people who carry particular, rare gene variants have much lower viral loads than other patients do."
The study analysed 996 men - 562 of whom were HIV positive - enrolled in the Chicago component of the Multicenter AIDS Cohort Study (MACS). Launched in 1984, MACS is a study of the natural and treated histories of HIV infection in men.
The researchers screened study 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, and the many different HLA alleles have different biological activities that affect the body's response to invasion.
In analysing the dozens of HLA-A and HLA-B alleles in the patients, the researchers identified some that conferred protection against HIV, while others left patients more susceptible.
However, immune system alleles are notoriously diverse, making it difficult to identify gene combinations that are important to patients' disease outcomes using traditional methods, Kepler said.
The researchers developed a novel statistical method, called minimum description length (MDL), to partition patients in a more detailed manner into disease progression groups based on their immune system genes. Although MDL has existed in theory, the research by Kepler and his colleagues represents the first time the method has been used for analyzing biomedical disease-association data.
"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. "We were therefore able to identify the optimum means of dividing patients into genetic categories that correspond to viral load."
The statistical classification of the patients revealed that the genetic combinations that conferred the greatest protection were also the least common gene variants in the patient population, the team reported. For example, African-American patients, who were underrepresented in the study and bore less common immune system alleles, exhibited lower viral loads.
"Greater protection against HIV was afforded by rare immune system alleles," Kepler said. "That suggests that HIV has adapted to attack the dominant alleles in the population. In other words, the virus goes after the bigger target." The results also suggest that the gene variants that confer protection against HIV will vary among human populations, according to their frequency, he said.
By screening patients' immune systems, physicians might ultimately identify those patients at the greatest risk for progressing to AIDS and prescribe treatments accordingly, Kepler added.
Further information on this website
Trachtenberg E et al. Advantage of rare HLA supertype in HIV disease progression Nature Medicine (advance publication online, June 22).