title: An extensive antigenic footprint underpins immunodominant TCR adaptability against a hypervariable viral determinant.
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.
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3000, Australia;
authors.forename: Usha K
authors.initials: UK
authors.lastname: Nivarthi
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3000, Australia;
authors.forename: Lars
authors.initials: L
authors.lastname: Kjer-Nielsen
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Richard
authors.initials: R
authors.lastname: Berry
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia;
authors.forename: Isabelle S
authors.initials: IS
authors.lastname: Lucet
authors.affiliation: Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia; School of Medicine, University of Queensland, Brisbane, Queensland 4006, Australia;
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3000, Australia;
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Tracy
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria 3010, Australia;
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Parkville, Victoria 3000, Australia;
authors.forename: David S
authors.initials: DS
authors.lastname: Bowden
authors.affiliation: Centre for Population Health, Burnet Institute, Melbourne, Victoria 3004, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria 3800, Australia; and Centre for Research Excellence into Injecting Drug Use, Burnet Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Margaret
authors.initials: M
authors.lastname: Hellard
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia; Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom; mandvi@unimelb.edu.au jamesm1@unimelb.edu.au Jamie.Rossjohn@monash.edu.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3000, Australia; mandvi@unimelb.edu.au jamesm1@unimelb.edu.au Jamie.Rossjohn@monash.edu.
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.affiliation: Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3000, Australia; mandvi@unimelb.edu.au jamesm1@unimelb.edu.au Jamie.Rossjohn@monash.edu.
authors.forename: Mandvi
authors.initials: M
authors.lastname: Bharadwaj
mesh_terms: D000940:Antigenic Variation / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D015795:HLA-B8 Antigen / Q000378:metabolism; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D015202:Protein Engineering; D055550:Protein Stability; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; C509422:HLA-B*08:01 antigen; D015795:HLA-B8 Antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D017361:Viral Nonstructural Proteins