title: The broad assessment of HCV genotypes 1 and 3 antigenic targets reveals limited cross-reactivity with implications for vaccine design.
abstract: OBJECTIVE
  Developing a vaccine that is cross-reactive between HCV genotypes requires data on T cell antigenic targets that extends beyond genotype-1. We characterised T cell immune responses against HCV genotype-3, the most common infecting genotype in the UK and Asia, and assessed within genotype and between genotype cross-reactivity.
  
  
  METHODS
  T cell targets were identified in 140 subjects with either acute, chronic or spontaneously resolved HCV genotype-3 infection using (1) overlapping peptides and (2) putative human leucocyte antigens (HLA)-class-I wild type and variant epitopes through the prior assessment of polymorphic HCV genomic sites associated with host HLA, in IFNγ-ELISpot assays. CD4+/CD8+ T cell subsets were defined and viral variability at T cell targets was determined through population analysis and viral sequencing. T cell cross-reactivity between genotype-1 and genotype-3 variants was assessed.
  
  
  RESULTS
  In resolved genotype-3 infection, T cells preferentially targeted non-structural proteins at a high magnitude, whereas in chronic disease T cells were absent or skewed to target structural proteins. Additional responses to wild type but not variant HLA predicted peptides were defined. Major sequence viral variability was observed within genotype-3 and between genotypes 1 and 3 HCV at T cell targets in resolved infection and at dominant epitopes, with limited T cell cross-reactivity between viral variants. Overall 41 CD4/CD8+ genotype-3 T cell targets were identified with minimal overlap with those described for HCV genotype-1.
  
  
  CONCLUSIONS
  HCV T cell specificity is distinct between genotypes with limited T cell cross-reactivity in resolved and chronic disease. Therefore, viral regions targeted in natural HCV infection may not serve as attractive targets for a vaccine that aims to protect against multiple HCV genotypes.
authors.affiliation: NDM, University of Oxford, Oxford, Oxfordshire, UK.
authors.forename: Annette
authors.identifier: http://orcid.org/0000-0002-7699-8140
authors.initials: A
authors.lastname: von Delft
authors.affiliation: NDM, University of Oxford, Oxford, Oxfordshire, UK.
authors.forename: Isla S
authors.initials: IS
authors.lastname: Humphreys
authors.affiliation: NDM, University of Oxford, Oxford, Oxfordshire, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Brown
authors.affiliation: NDM, University of Oxford, Oxford, Oxfordshire, UK.
authors.forename: Katja
authors.initials: K
authors.lastname: Pfafferott
authors.affiliation: Institute of Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia School of Medicine and Pharmacology, Harry Perkins Institute, University of Western Australia, Western Australia, Australia School of Pathology and Laboratory Medicine, University of Western Australia, Western Australia, Australia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Lucas
authors.affiliation: NDM, University of Oxford, Oxford, Oxfordshire, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.affiliation: Ragon Institute of MGH, Boston, Massachusetts, USA.
authors.forename: Georg M
authors.initials: GM
authors.lastname: Lauer
authors.affiliation: John Hopkins University, Baltimore, Maryland, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Cox
authors.affiliation: Institute of Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia School of Anatomy, Physiology and Human Biology, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.affiliation: NDM, University of Oxford, Oxford, Oxfordshire, UK.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Barnes
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003429:Cross Reactions; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics* / Q000276:immunology; D006526:Hepatitis C / Q000276:immunology / Q000821:virology*; D018936:Hepatitis C Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics* / Q000276:immunology; D014761:Viral Hepatitis Vaccines; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D018936:Hepatitis C Antigens; D014761:Viral Hepatitis Vaccines; D017361:Viral Nonstructural Proteins
keywords: CELLULAR IMMUNITY; GENOTYPE; HCV