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.
In the 25 years, it has known that a few individuals infected with HIV are naturally able to suppress the virus with their immune systems; but a highly functional CD8 T cell response has suggested as one probable mechanism. So 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 common in HIV controllers but not in individuals with progressive HIV infection.
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.”All proteins fold into their ultimate, three-dimensional structure through a series of bonds between amino acids; so we can mathematically represent proteins as a network of connections between amino acids.
Amino acids in the protein
Therefore 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 able to calculate network scores for each amino acid; reflecting the number and relative importance of bonds with other amino acids in the protein. But the more highly networking an amino acid was, the less likely it was to in thousands of viral sequences taken from patients; so implying that highly networked residues were important to viral function.
This study implies that HIV controllers are able to keep the virus in check with highly functional CD8 T cell responses directed against critical peptides; which cannot mutate without costly effects on the virus’s ability to replicate; allowing persistent killing of infected cells by CD8 T cells,” says Gaiha, an instructor in Medicine at Harvard Medical School (HMS). “They have working on the development of a vaccine based on these findings, incorporating highly peptides by versions of HLA that are common throughout the global population.”