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| Article Authors: | Juandy Jo; Ulrike Aichele; Nadine Kersting; Rahel Klein; Peter Aichele; Emmanuel Bisse; Andrew K Sewell; Hubert E Blum; Ralf Bartenschlager; Volker Lohmann; Robert Thimme |
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| Article Title: | Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication using a novel immunological model. |
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| Reference ID: | 1014087 |
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| Abstract: | BACKGROUND & AIMS: Virus-specific CD8+ T cells are required for the control of hepatitis C virus (HCV) infection. We investigated the extent to which different effector functions of CD8+ T cells contribute to the inhibition of viral replication. METHODS: We developed a novel immunologic model by stably transducing the HLA-A2 gene into the replicon system, matching the epitope sequence of the replicon to the sequence targeted by an HCV-specific CD8+ T-cell clone. Luciferase activity was then measured to quantitate HCV RNA replication. RESULTS: HCV-specific CD8+ T cells strongly inhibited viral replication, through cytolytic and noncytolytic mechanisms, in a dose-dependent manner. HCV replication was almost completely inhibited at an effector-to-target ratio of 1:1 with significant cytotoxicity; however, >95% viral inhibition occurred at ratios as low as 1:100. Importantly, no cytotoxicity was observed at low effector-to-target ratios, indicating a dominant effect of noncytolytic effector functions that was confirmed by Transwell experiments. Neutralization experiments revealed that interferon gamma mediates the noncytolytic inhibition. CONCLUSIONS: Only a very few HCV-specific CD8+ T cells are required to inhibit HCV replication; inhibition occurs primarily by noncytolytic effector functions. |
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| Affiliations: | Department of Medicine II, University Hospital Freiburg, and Faculty of Biology, Spemann Graduate School of Biology and Medicine, Albert Ludwigs University, Freiburg, Germany. |
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| Date: | 2009 |
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| Reference Type: | Literature |
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| PubMed ID: | 19185579 |
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| Journal: | Gastroenterology |
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| Journal Volume: | 136 |
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| Article Pages: | 1391-401 |
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| Journal ISSN: | 1528-0012 |
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| Article Chemical List: | Epitopes, T-Lymphocyte;HLA-A2 Antigen;NS-5 protein, hepatitis C virus;Viral Nonstructural Proteins;Interferon-gamma |
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| Article MeSH List: | CD8-Positive T-Lymphocytes(metabolism; physiology; virology); Carcinoma, Hepatocellular(metabolism; pathology); Cell Line, Tumor; Epitopes, T-Lymphocyte(genetics); HLA-A2 Antigen(genetics; metabolism); Hepacivirus(physiology); Hepatitis C(immunology; metabolism); Humans; Interferon-gamma(metabolism); Liver Neoplasms(metabolism; pathology); Models, Immunological; Replicon(genetics); Transduction, Genetic; Viral Nonstructural Proteins(genetics); Virus Replication(physiology) |
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| Curation Last Updated: | 2010-10-26 01:59:51 |
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