Publications & Reports

An extensive antigenic footprint underpins immunodominant TCR adaptability against a hypervariable viral determinant.

Nivarthi UK, Gras S, Kjer-Nielsen L, Berry R, Lucet IS, Miles JJ, Tracy SL, Purcell AW, Bowden DS, Hellard M, Rossjohn J, McCluskey J, Bharadwaj M
Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3000, Australia;


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-B0801-restricted epitope (1395HSKKKCDEL1403 [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-B0801-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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  • Journal: Journal of Immunology
  • Published: 29/10/2014
  • Volume: 193
  • Issue: 11
  • Pagination: 5402-5413