Tiny differences in five amino acids in HLA-B, a protein, are linked to whether people can control levels of HIV (human immunodeficiency virus) with just their immune systems, an international team of researchers wrote in the journal Science. These small variants in the protein appear to alert the immune system that there is an infection.
Co-senior author Bruce Walker, MD, director of the Ragon Institute, said:
We found that, of the three billion nucleotides in the human genome, just a handful make the difference between those who can stay healthy in spite of HIV infection and those who, without treatment, will develop AIDS. Understanding where this difference occurs allows us to sharpen the focus of our efforts to ultimately harness the immune system to defend against HIV.
Co-senior author, Paul de Bakker, PhD, of the Broad Institute and Brigham and Women's Hospital, said:
Earlier studies had showed that certain genes involved with the HLA system were important for HIV control. But they couldn't tell us exactly which genes were involved and how they produced this difference. Our findings take us not only to a specific protein, but to a part of that protein that is essential to its function.
The authors explain that approximately 1 in every 300 patients infected with HIV is naturally able to undermine viral replication just with their immune system, resulting in permanent very low viral loads.
Such people are known as HIV Controllers, or simply Controllers.
Florencia Pereyra, MD, at the Ragon Institute, set up the International HIV Controllers Study in 2006, in order to determine what genetic features drove this unique ability to keep viral loads down naturally. Their aim was to enroll 1,000 HIV controllers from clinics and centers of research worldwide. So far, 1,500 controllers have been enrolled and the goal was upped to 2,000 of them.
This study started with a GWAS (genome-wide association study) of nearly 1,000 controllers and 2,600 patients with progressive HIV infection, provided through a collaboration with the AIDS Clinical Trials Group.
The GWAS located about 300 sites that were statistically linked to HIV immune control - all 300 sites were in chromosome 6, in the regions that code for HLA proteins. The scientists eventually pinned down the gene sites to four, but could not tell whether they were just located close to casual variants or really had an impact on viral control.
They could not fully sequence that genome region in all participants. They used a process developed by Sherman Jia to identify specific amino acids - directly testing those sites linked 5 amino acids within the HLA-B protein with variations in viral control. Sherman Jia is a medical student in the Harvard-MIT Health Sciences and Technology program.
HLA-B plays a vital role in the immune system's process of identifying and destroying cells which are infected by virus. HLA-B usually attaches onto viral peptides (protein segments) inside the cell and carries them to the cell's membrane where CD8 "killer" T cells are flagged to destroy the infected cell.
All the 5 identified amino acid sites are in the lining of the binding pocket - the part of the HLA-B protein that grabs and displays the viral peptides.
Bakker said:
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. 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.
Walker added:
HIV is slowly revealing its secrets, and this is yet another. Knowing how an effective immune response against HIV is generated is an important step toward replicating that response with a vaccine. We have a long way to go before translating this into a treatment for infected patients and a vaccine to prevent infection, but we are an important step closer.
The researchers stress that this study could not have occurred without the participation of the HIV controllers who enrolled in the study. A significant number of them travelled a great distance to Boston for tests.
Pereyra said:
The enthusiasm among the patients we have enrolled and the HIV providers who referred them has been amazing. They tell us that being part of this collaborative study means a lot to them.
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