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Analysis of CD8+ T-Cell-Mediated Inhibition of Hepatitis C Virus Replication Using a Novel Immunological Model

Jo, J., Aichele, U., Kersting, N., Klein, R., Aichele, P., Bisse, E., Sewell, Andrew K., Blum, H. E., Bartenschlager, R., Lohmann, V. and Thimme, R. 2009. Analysis of CD8+ T-Cell-Mediated Inhibition of Hepatitis C Virus Replication Using a Novel Immunological Model. Gastroenterology 136 (4) , pp. 1391-1401. 10.1053/j.gastro.2008.12.034

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
R Medicine > RM Therapeutics. Pharmacology
Publisher: Elsevier
ISSN: 0016-5085
Last Modified: 04 Jun 2017 01:55

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