Liu, Yu Chih, Chen, Zhenjun, Neller, Michelle A., Miles, John J., Purcell, Anthony W., McCluskey, James, Burrows, Scott R., Rossjohn, Jamie, and Gras, Stephanie (2014) A molecular basis for the interplay between T cells, viral mutants, and human leukocyte antigen micropolymorphism. Journal of Biological Chemistry, 289 (24). pp. 16688-16698.

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Abstract

Mutations within T cell epitopes represent a common mechanism of viral escape from the host 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 (⁴⁰⁷)HPVGEADYFEY(⁴¹⁷) epitope from Epstein-Barr virus 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 Epstein-Barr virus.

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