title: Functional differences in hepatitis C virus nonstructural (NS) 3/4A- and 5A-specific T cell responses.
abstract: The hepatitis C virus nonstructural (NS) 3/4A and NS5A proteins are major targets for the new direct-acting antiviral compounds. Both viral proteins have been suggested as modulators of the response to the host cell. We have shown that NS3/4A- and NS5A-specific T cell receptors confer different effector functions, and that killing of NS3/4A-expressing hepatocytes is highly dependent on IFN-γ. We here characterize the functional differences in the T cell responses to NS3/4A and NS5A. NS3/4A- and NS5A-specific T cells could be induced at various frequencies in wild-type-, NS3/4A-, and NS5A-transgenic mice. Priming of NS5A-specific T cells required a high DNA dose, and was unlike NS3/4A dependent on both CD4(+) and CD8(+) T cells, but less influenced by CD25(+)/GITR(+) regulatory T cells. The presence of IL-12 greatly improved specific CD8(+) T cell priming by NS3/4A but not by NS5A, suggesting a less dependence of IFN-γ for NS5A. This notion was supported by the observation that NS5A-specific T cells could eliminate NS5A-expressing hepatocytes also in the absence of IFN-γ-receptor-2. This supports that NS3/4A- and NS5A-specific T cells become activated and eliminate antigen expressing, or infected hepatocytes, by distinct mechanisms, and that NS5A-specific T cells show an overall less dependence of IFN-γ.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Holmström
authors.affiliation: Department of Dental Medicine, Karolinska Institutet, Huddinge, S-141 04 Stockholm, Sweden.
authors.forename: Margaret
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.|Department of Dental Medicine, Karolinska Institutet, Huddinge, S-141 04 Stockholm, Sweden.
authors.forename: Anangi
authors.initials: A
authors.lastname: Balasiddaiah
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Sällberg
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Gustaf
authors.initials: G
authors.lastname: Ahlén
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, F68, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Frelin
mesh_terms: D000818:Animals; D007371:Interferon-gamma / Q000378:metabolism; D053765:Interleukin-12 Subunit p35 / Q000378:metabolism; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; D012324:RNA-Dependent RNA Polymerase
chemical_list: D007371:Interferon-gamma; D053765:Interleukin-12 Subunit p35; D017361:Viral Nonstructural Proteins; C508859:Il12a protein, mouse; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080107:NS4B protein, flavivirus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase