CINCINNATI—Researchers in a multi-center, national study have discovered that certain variants in a human protein may alert the immune system to infection, helping some patients with HIV control the illness without medications.
This finding could help researchers one day develop a vaccine for HIV.
This report was led by Bruce Walker, MD, director of the Ragon Institute of Massachusetts General Hospital, MIT and Harvard, and Paul de Bakker, PhD, director of the Genomics Program of the Harvard University Center for AIDS Research, and is featured in the Nov. 4 online edition of the journal Science.
Kay Johnson, MD, associate professor of medicine at UC and a co-author of the study, says the finding shows differences in five amino acids in a protein called HLA-B, which is associated with the ability of HIV-infected individuals to control or not control viral levels using only their immune system.
"There are roughly 3 billion nucleotides in the human genome, and there are only a few that make the difference between individuals who can stay healthy with HIV infection and those who will develop AIDS without treatment,” she says. "Understanding this difference allows us to take the first steps in truly understanding the immune system and find ways to direct it to defend against HIV.”
Johnson says researchers were aware that a small minority of individuals infected with HIV are naturally able to suppress the replication of the virus with their immune system.
To identify genetic differences that may underlie this rare ability, Florencia Pereyra, MD, of the Ragon Institute, established the International HIV Controllers Study in 2006, with a goal of enrolling 1,000 HIV controllers. The study has since expanded.
This study began by testing roughly 1,000 controllers and 2,600 patients with progressive HIV using a genome-wide association study (GWAS)—testing variations at a million points in the human genome. The test identified about 300 sites that were 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 indication of whether or not those differences affected viral control was unclear. A process developed by Sherman Jia, a medical student in the Harvard-MIT Health Sciences and Technology program, pinpointed the specific amino acids. Testing those sites uncovered five amino acids in the HLA-B protein that were associated with differences in viral control.
"Usually, HLA-B grabs onto the protein segments of viruses, called peptides, that are inside the cell and carries them to the cell membrane where they flag the infected cell for destruction by ‘killer,’ or CD8, T cells,” Johnson explains. "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.”
She adds that amino acid variation within the binding pocket will affect shape and structure, causing some peptides to be effective and others not.
"This work demonstrates that the variants could make an important difference in the patient’s ability to control HIV by altering how HLA-B presents peptides from the virus in the immune system,” she says. "Knowing how the immune system responds effectively against HIV is an important step in replicating that response with a vaccine. There is still much more to uncover, but this is truly a step in the right direction.”
Original support for the International HIV Controllers study came through a 2006 grant from the Mark and Lisa Schwartz Foundation, and the study was expanded in 2008 through the support of the Bill and Melinda Gates Foundation.