title: Anti-hepatitis C virus T-cell immunity in the context of multiple exposures to the virus.
abstract: Characterisation of Hepatitis C virus (HCV)-specific CD8+ T-cell responses in the context of multiple HCV exposures is critical to identify broadly protective immune responses necessary for an effective HCV vaccine against the different HCV genotypes. However, host and viral genetic diversity complicates vaccine development. To compensate for the observed variation in circulating autologous viruses and host molecules that restrict antigen presentation (human leucocyte antigens; HLA), this study used a reverse genomics approach that identified sites of viral adaptation to HLA-restricted T-cell immune pressure to predict genotype-specific HCV CD8+ T-cell targets. Peptides representing these putative HCV CD8+ T-cell targets, and their adapted form, were used in individualised IFN-γ ELISpot assays to screen for HCV-specific T-cell responses in 133 HCV-seropositive subjects with high-risk of multiple HCV exposures. The data obtained from this study i) confirmed that genetic studies of viral evolution is an effective approach to detect novel in vivo HCV T-cell targets, ii) showed that HCV-specific T-cell epitopes can be recognised in their adapted form and would not have been detected using wild-type peptides and iii) showed that HCV-specific T-cell (but not antibody) responses against alternate genotypes in chronic HCV-infected subjects are readily found, implying clearance of previous alternate genotype infection. In summary, HCV adaptation to HLA Class I-restricted T-cell responses plays a central role in anti-HCV immunity and multiple HCV genotype exposure is highly prevalent in at-risk exposure populations, which are important considerations for future vaccine design.
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
authors.forename: Katja
authors.initials: K
authors.lastname: Pfafferott
authors.affiliation: School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Pooja
authors.initials: P
authors.lastname: Deshpande
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McKinnon
authors.affiliation: Centre for Forensic Science, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Shahzma
authors.initials: S
authors.lastname: Merani
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lucas
authors.affiliation: Microsoft Research, Microsoft, Redmond, Washington, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; Division of Infectious Diseases, Department of Medicine and Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia; School of Medicine and Pharmacology, Harry Perkins Institute, University of Western Australia, Crawley, Western Australia, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Lucas
mesh_terms: D000483:Alleles; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D015331:Cohort Studies; D058501:Enzyme-Linked Immunospot Assay; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry; D005260:Female; D023281:Genomics; D005838:Genotype; D006680:HLA Antigens / Q000276:immunology; D016174:Hepacivirus; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D008297:Male; D010455:Peptides / Q000737:chemistry
chemical_list: D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D010455:Peptides