Researchers have revealed that the rare ability of some individuals to control HIV infection without the need for medications may be explained by the tiny variants in a protein that alerts the immune system to the presence of infection.
An international research team led by investigators from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard and from the Broad Institute of MIT and Harvard describe finding that differences in five amino acids in a protein called HLA-B are associated with whether or not HIV-infected individuals can control viral levels with their immune system only.
The current investigation began with a genome-wide association study (GWAS) of almost 1,000 controllers and 2,600 individuals with progressive HIV infection, through a collaboration with the AIDS Clinical Trials Group. The GWAS, which tests variations at a million points in the human genome, identified some 300 sites that were statistically associated with immune control of HIV, all in regions of chromosome 6 that code for HLA proteins.
Further analysis narrowed the number of gene sites to four but could not indicate whether those differences actually affected viral control or were just located near the causal variants. Fully sequencing that genome region in all participants was not feasible, but a process developed by Sherman Jia - a medical student in the Harvard-MIT Health Sciences and Technology program, working with de Bakker at the Broad - pinpointed specific amino acids; and directly testing those sites associated five amino acids in the HLA-B protein with differences in viral control.
HLA-B is essential to the process by which the immune system recognizes and destroys virus-infected cells. Usually HLA-B grabs onto viral protein segments called peptides that are inside the cell and carries them to the cell membrane where they essentially flag the infected cell for destruction by CD8 "killer" T cells. The portion of the HLA-B protein that grabs and displays viral peptides is called the binding pocket, and all of the five identified amino acid sites are in the lining of the binding pocket.
"Amino acid variation within the HLA-B binding pocket will impact its shape and structure, probably resulting in some peptides being presented effectively and others not," de Bakker said.
"Our work demonstrates that these variants could make a crucial difference in the individual's ability to control HIV by changing how HLA-B presents peptides from this virus to the immune system."
The report has been published in Science.