title: TCR-redirected human T cells inhibit hepatitis C virus replication: hepatotoxic potential is linked to antigen specificity and functional avidity.
abstract: Virus-specific CTL with high levels of functional avidity have been associated with viral clearance in hepatitis C virus (HCV) infection and with enhanced protective immunity. In chronic HCV infection, lack of antiviral CTL is frequently observed. In this study, we aim to investigate novel HCV TCRs that differ in Ag specificity. This involved isolating new HCV-specific murine TCRs that recognize a conserved HLA-A2-restricted CTL epitope within the nonstructural protein (NS) 5A viral protein and comparing them with TCRs recognizing another conserved CTL target in the NS3 viral protein. This was done by expressing the TCRs in human T cells and analyzing the function of the resulting TCR-transduced T cells. Our result indicates that these TCRs are efficiently assembled in transduced human T cells. They recognize peptide-loaded targets and demonstrate polyfunctional features such as IL-2, IFN-γ, and TNF-α secretion. However, in contrast to NS3-specific TCRs, the NS5A TCR-transduced T cells consist of a smaller proportion of polyfunctional T cells and require more peptide ligands to trigger the effector functions, including degranulation. Despite the differences, NS5A TCRs show effective inhibition of HCV replication in human hepatoma cells with persistent HCV RNA replication. Moreover, cellular injury demonstrated by aspartate aminotransferase release and cell death is less significant in the hepatoma cells following coincubation with NS5A TCR-transduced T cells, which is a property consistent with noncytotoxic antiviral CTLs. Our results suggest that HCV TCR-transduced T cells may be promising for the treatment of patients with chronic HCV infections.
authors.affiliation: Department of Dental Medicine, Karolinska Institutet, Huddinge 141 04, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Pasetto
authors.forename: Lars
authors.initials: L
authors.lastname: Frelin
authors.forename: Soo
authors.initials: S
authors.lastname: Aleman
authors.forename: Fredrik
authors.initials: F
authors.lastname: Holmström
authors.forename: Anette
authors.initials: A
authors.lastname: Brass
authors.forename: Gustaf
authors.initials: G
authors.lastname: Ahlén
authors.forename: Erwin D
authors.initials: ED
authors.lastname: Brenndörfer
authors.forename: Volker
authors.initials: V
authors.lastname: Lohmann
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.forename: Matti
authors.initials: M
authors.lastname: Sällberg
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
authors.forename: Margaret
authors.initials: M
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000502:physiology* / Q000633:toxicity; D005260:Female; D018014:Gene Transfer Techniques; D016174:Hepacivirus / Q000276:immunology* / Q000472:pathogenicity*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic / Q000379:methods; D014779:Virus Replication / Q000235:genetics / Q000276:immunology*
chemical_list: D000998:Antiviral Agents; D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell