A molecular basis for the interplay between T cells, viral mutants, and human leukocyte antigen micropolymorphism

Mutations within T cell epitopes represent a common mechanism of viral escape from the host s protective immune response. The diverse T cell repertoire and the extensive human leukocyte antigen (HLA) polymorphism across populations is the evolutionary response to viral mutation. However, the molecular basis underpinning the interplay between HLA polymorphism, the T cell repertoire and viral escape is unclear. Here, we investigate the T cell response to a HLA-B*35:01 and HLA-B*35:08 restricted 407HPVGEADYFEY417 epitope (HPVG) from Epstein-Barr virus (EBV), and naturally occurring variants at positions 4 and 5 thereof. Each viral variant differently impacted on the epitope s flexibility and conformation when bound to HLA-B*35:08 or HLA-B*35:01. We provide a molecular basis for understanding how the single residue polymorphism that discriminates between HLA-B*35:01/08 profoundly impacts on T cell receptor recognition. Surprisingly, one viral variant (P5-Glu to P5-Asp) effectively changed restriction preference from HLA-B*35:01 to HLA-B*35:08. Collectively, our study portrays the interplay between the T cell response, viral escape and HLA polymorphism, whereby HLA polymorphism enables altered presentation of epitopes from different strains of EBV.