Nivarthi, Usha K., Gras, Stephanie, Kjer-Nielsen, Lars, Berry, Richard, Lucet, Isabelle S., Miles, John J., Tracy, Samantha L., Purcell, Anthony W., Bowden, David S., Hellard, Margaret, Rossjohn, Jamie, McCluskey, James, and Bharadwaj, Mandvi (2014) An extensive antigenic footprint underpins immunodominant TCR adaptability against a hypervariable viral determinant. Journal of Immunology, 193 (11). pp. 5402-5413.

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Abstract

Mutations in T cell epitopes are implicated in hepatitis C virus (HCV) persistence and can impinge on vaccine development. We recently demonstrated a narrow bias in the human TCR repertoire targeted at an immunodominant, but highly mutable, HLA-B*0801-restricted epitope ((1395)HSKKKCDEL(1403) [HSK]). To investigate if the narrow TCR repertoire facilitates CTL escape, structural and biophysical studies were undertaken, alongside comprehensive functional analysis of T cells targeted at the natural variants of HLA-B*0801-HSK in different HCV genotypes and quasispecies. Interestingly, within the TCR-HLA-B*0801-HSK complex, the TCR contacts all available surface-exposed residues of the HSK determinant. This broad epitope coverage facilitates cross-genotypic reactivity and recognition of common mutations reported in HCV quasispecies, albeit to a varying degree. Certain mutations did abrogate T cell reactivity; however, natural variants comprising these mutations are reportedly rare and transient in nature, presumably due to fitness costs. Overall, despite a narrow bias, the TCR accommodated frequent mutations by acting like a blanket over the hypervariable epitope, thereby providing effective viral immunity. Our findings simultaneously advance the understanding of anti-HCV immunity and indicate the potential for cross-genotype HCV vaccines.

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