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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.","bibjson":{"author":[{"initials":"UK","lastname":"Nivarthi","name":"Nivarthi UK"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"L","lastname":"Kjer-Nielsen","name":"Kjer-Nielsen L"},{"initials":"R","lastname":"Berry","name":"Berry R"},{"initials":"IS","lastname":"Lucet","name":"Lucet IS"},{"initials":"JJ","lastname":"Miles","name":"Miles JJ"},{"initials":"SL","lastname":"Tracy","name":"Tracy SL"},{"initials":"AW","lastname":"Purcell","name":"Purcell AW"},{"initials":"DS","lastname":"Bowden","name":"Bowden DS"},{"initials":"M","lastname":"Hellard","name":"Hellard M"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"J","lastname":"McCluskey","name":"McCluskey J"},{"initials":"M","lastname":"Bharadwaj","name":"Bharadwaj M"}],"identifier":[{"id":"10.4049/jimmunol.1401357","type":"doi"},{"id":"25355921","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. Immunol.","name":""},"pages":[null],"title":"An Extensive Antigenic Footprint Underpins Immunodominant TCR Adaptability against a Hypervariable Viral Determinant.","type":"article","url":"http://www.jimmunol.org/lookup/doi/10.4049/jimmunol.1401357","volume":[null],"year":[2014]},"in_pmc":"N","in_pmce":"N","open_access":"N"},"resolution":"1.70","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/4qrq"},"rcsb":{"url":"https://www.rcsb.org/structure/4qrq"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":null,"title":"HLA-B*08:01 binding \"HSKKKCDEL\" at 1.70Å resolution","unique_chain_count":3}}