Investigators at the Ragon Institute of MGH, MIT, and Harvard have used a novel approach to identify specific amino acids in the protein structure of HIV that appear critical to the ability of the virus to function and replicate. They also have found that the immune systems of individuals naturally able to control HIV infection target these amino acids with pathogen-killing CD8 T cells, an ability seen even in controllers who do not carry versions of the HLA-B protein previously associated with HIV control. The report appears in the May 3 issue of Science and could guide the development of broadly protective vaccines to prevent and suppress HIV infection.
In the 25 years it has been known that a few individuals infected with HIV are naturally able to suppress the virus with their immune systems, a highly functional CD8 T cell response has been suggested as one probable mechanism. A 2010 Ragon Institute study found that specific variants of the HLA-B protein—which carries viral peptides to the surface of infected cells and presents them to the immune system, marking the cell for destruction by CD8 T cells—were common in HIV controllers but not in individuals with progressive HIV infection. Five amino acids in the most common control-associated variant, HLA-B57, were found in the lining of the binding pocket, the portion of the protein that grabs and displays viral peptides. But subsequent research identified a few controllers who do not carry HLA-B57, indicating that other mechanisms could be involved.
For the current study, the Ragon team used structure-based network analysis—a novel approach to examine the complex, structural bonds within and among viral proteins—to identify residues (specific amino acids within a peptide) crucial to viral function
Applying network analysis to information obtained from the Protein Data Bank on the structure of 12 of the 15 proteins that make up HIV, the investigators were able to calculate network scores for each amino acid, reflecting the number and relative importance of bonds with other amino acids in the protein. The more highly networked an amino acid was, the less likely it was to be mutated in thousands of viral sequences taken from patients, implying that highly networked residues were important to viral function.
To test that implication, the investigators engineered mutations into amino acids with high and low network scores and found that mutating highly networked residues substantially impaired the ability of HIV to infect cells and replicate. In contrast, mutating amino acids with low network scores had little or no impact on viral infectivity. The Gag p24 protein, which is important for formation of the virus’s protein shell, had the highest frequency of networked amino acids, which supports previous studies finding that it was more sensitive than other HIV proteins to the effects of mutation and that T-cell responses targeting Gag p24 were associated with lower viral levels.
