Unusual viral ligand with alternative interactions is presented by HLA‐Cw4 in human respiratory syncytial virus‐infected cells

Short viral antigens bound to human major histocompatibility complex (HLA) class I molecules are presented on infected cells. Vaccine development frequently relies on synthetic peptides to identify optimal HLA class I ligands. However, when natural peptides are analyzed, more complex mixtures are found. By immunoproteomics analysis, we identify in this study a physiologically processed HLA ligand derived from the human respiratory syncytial virus matrix protein that is very different from what was expected from studies with synthetic peptides. This natural HLA‐Cw4 class I ligand uses alternative interactions to the anchor motifs previously described for its presenting HLA‐Cw4 class I molecule. Finally, this octameric peptide shares its C‐terminal core with the H‐2Db nonamer ligand previously identified in the mouse model. These data have implications for the identification of antiviral cytotoxic T lymphocyte responses and for vaccine development.