title: Immunogenicity and cross-reactivity of a representative ancestral sequence in hepatitis C virus infection.
abstract: Vaccines designed to prevent or to treat hepatitis C viral infection must achieve maximum cross-reactivity against widely divergent circulating strains. Rational approaches for sequence selection to maximize immunogenicity and minimize genetic distance across circulating strains may enhance vaccine induction of optimal cytotoxic T cell responses. We assessed T cell recognition of potential hepatitis C virus (HCV) vaccine sequences generated using three rational approaches: combining epitopes with predicted tight binding to the MHC, consensus sequence (most common amino acid at each position), and representative ancestral sequence that had been derived using bayesian phylogenetic tools. No correlation was seen between peptide-MHC binding affinity and frequency of recognition, as measured by an IFN-γ T cell response in HLA-matched HCV-infected individuals. Peptides encoding representative, consensus, and natural variant sequences were then tested for the capacity to expand CD8 T cell populations and to elicit cross-reactive CD8 T cell responses. CD8(+) T cells expanded with representative sequence HCV generally more broadly and robustly recognized highly diverse circulating HCV strains than did T cells expanded with either consensus sequence or naturally occurring sequence variants. These data support the use of representative sequence in HCV vaccine design.
authors.affiliation: Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Kelly P
authors.initials: KP
authors.lastname: Burke
authors.forename: Supriya
authors.initials: S
authors.lastname: Munshaw
authors.forename: William O
authors.initials: WO
authors.lastname: Osburn
authors.forename: Jordana
authors.initials: J
authors.lastname: Levine
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Ray
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Cox
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D015331:Cohort Studies; D016384:Consensus Sequence / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism*; D011446:Prospective Studies; D014761:Viral Hepatitis Vaccines / Q000138:chemical synthesis / Q000276:immunology / Q000378:metabolism
chemical_list: D006680:HLA Antigens; D010446:Peptide Fragments; D014761:Viral Hepatitis Vaccines