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. ORCID: https://orcid.org/0000-0003-3194-3135, 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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Abstract

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 Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General) R Medicine > RM Therapeutics. Pharmacology
Publisher:	Elsevier
ISSN:	0016-5085
Last Modified:	17 Oct 2022 09:52
URI:	https://orca.cardiff.ac.uk/id/eprint/6018

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