Variations in an immune-system gene account for at least part of the uncanny ability of some people to withstand an HIV infection without developing AIDS, researchers report online November 4 in Science. The study confirms past data linking the gene, called HLA-B, to HIV defense and narrows researchers’ focus to molecular changes brought on by particular variations in the gene.
About one in 300 people with HIV are “elite controllers.” Though infected with the virus, their immune systems control the disease such that it rarely progresses, even without medicine. Scientists have long thought that finding the genetic peculiarities underlying this protection could help to create drugs or a vaccine against HIV. Recently, scientists found that elite controllers make excess amounts of a protein called p21, which might contribute to protection (SN: 11/20/10, p. 9).
Previous research had hinted that HLA gene variations played a role in elite controllers by influencing a patient’s HIV viral load and disease progression. HLA genes encode immune proteins called human leukocyte antigens, which are central to immune function.
In the new study, a multinational consortium of researchers identified more than 1 million genetic variations in blood samples from people with HIV, some elite controllers and some not. The scientists were able to spot more than 300 variations that differed substantially between the groups, says study coauthor Paul de Bakker, a geneticist at Harvard Medical School and Brigham and Women’s Hospital in Boston.
For example, a variant called HLA-B*57:01 showed up five times as often in controllers as in the others. Several variants of other genes appeared two to four times as often in controllers as well, but alternate forms of the HLA-B gene stood out in the analysis.
The HLA-B protein comes in many varieties, each encoded by a slightly different blueprint — a variation — of the HLA-B gene. The protein provides an essential immune function, collecting viral fragments in cells and displaying them on the cell surface for inspection by marauding immune enforcers called CD8 T cells, which give each protein a thumbs up or thumbs down. If the CD8 T cell disapproves of a protein fragment, the whole cell gets destroyed. While it may seem drastic to tag a cell for disposal, the extreme measures stop a virus before it can commandeer the cell to mass-produce more virus, says study coauthor Bruce Walker, an immunologist at Harvard Medical School and Massachusetts General Hospital in Boston.
“I think this is a really good paper. It’s very interesting,” says Alasdair Leslie, an immunologist at University of Oxford in England, whose group did earlier work linking CD8 T cell function to HLA proteins. “This strengthens the argument that HLA [variations] and presumably CD8 T cell responses are important,” he says. “It does give hope to the idea that harnessing this response in a vaccine could work.”
By analyzing the structure of the HLA-B gene variants and noting which were linked to protection against HIV, the researchers were able to zero in on a handful of amino acids — the molecular building blocks of proteins — that are instrumental in the all-important binding of HLA-B proteins to HIV fragments in a cell.
“This is a really exciting step toward a kind of pie-in-the-sky goal,” says statistical geneticist Alison Motsinger-Reif of North Carolina State University in Raleigh. Elite controllers represent a medical mystery, she says. “If we can understand what’s different about their biology, it will open up new targets [for HIV] drugs or vaccines.”
This molecular precision represents new terrain for scientists seeking to explain how controllers stay healthy, because it reveals what these amino acids are and even where they sit on an HLA-B protein, de Bakker says.
But that still doesn’t explain how they work.
“We’ve been looking for needles in a haystack,” Walker says. “Now we need to interrogate the needles.”