title: Polyfunctional CD8(+) T cells are associated with the vaccination-induced control of a novel recombinant influenza virus expressing an HCV epitope.
abstract: In hepatitis C virus (HCV) infection, CD8(+) T cell responses have been shown to be important in viral clearance. Examining the efficacy of CD8(+) T cell vaccines against HCV has been limited by the lack of an HCV infectious model in mice and the differences between MHC restriction in humans and mice. Using HLA-A2 transgenic HHD mice, we demonstrate that intranasally delivered Pam2Cys-based lipopeptides containing HLA-A2-restricted HCV epitopes can induce polyfunctional CD8(+) T cell responses in several organs including the liver. To examine the activity of these responses in an infectious context, we developed a recombinant influenza virus that expresses the NS5B(2594-2602) epitope from non-structural protein 5B of hepatitis C virus (PR8-HCV(NS5B)). We showed that mice inoculated with a lipopeptide containing the NS5B epitope had reduced viral loads following challenge with the PR8-HCV(NS5B) virus. This reduction was associated with the induction of NS5B(2594-2602)-specific IFN-γ and TNF-α co-producing CD8(+) T cells. The T cell receptor usage in the NS5B(2594-2602) response was found to exhibit a Vβ8.1/8.2 bias that was characterized by a narrow repertoire and a common CDR3β motif. This work has identified CD8(+) T cell functions induced by lipopeptides that are associated with viral control and demonstrate the potential of lipopeptide-based vaccines as candidates for treatment of HCV infection.
authors.affiliation: Department of Microbiology & Immunology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Amabel C L
authors.initials: AC
authors.lastname: Tan
authors.forename: Emily M Y
authors.initials: EM
authors.lastname: Eriksson
authors.forename: Katherine
authors.initials: K
authors.lastname: Kedzierska
authors.forename: Georgia
authors.initials: G
authors.lastname: Deliyannis
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Valkenburg
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zeng
authors.forename: David C
authors.initials: DC
authors.lastname: Jackson
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009975:Orthomyxoviridae / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014761:Viral Hepatitis Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*
chemical_list: D000939:Epitopes; D014409:Tumor Necrosis Factor-alpha; D014614:Vaccines, Synthetic; D014761:Viral Hepatitis Vaccines; D007371:Interferon-gamma