Cytotoxic T lymphocytes (CTL) select HIV variants that encode mutations in peptide epitopes presented by HLA. Studying HLA-associated viral polymorphisms may therefore elucidate characteristics of effective CTL responses. Using population-level data, we identified 2100 HLA-associated polymorphisms located throughout the HIV proteome. In 9-mer epitopes, viral mutations at HLA anchor residues occurred two-fold more frequently than expected and reduced predicted peptide-HLA binding affinity by ten-fold. Epitopes presented by more protective HLA displayed greater enrichment of anchor residue mutations. CTL epitope recognition is determined by its T-cell receptor (TCR). To assess the impact of epitope mutations on TCR signaling, we implemented an in vitro reporter cell assay. This method was validated using a TCR specific for the HLA-A*02:01-FK10 peptide (FLGKIWPSYK), and proved sensitive, scalable, and robust. Alanine mutants of the TCR and peptide variants identified an interaction between FK10 position 4 and TCR alpha CDR3 that may be critical for signaling.
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