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.
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.
Authors: Elisavet Serti; Jens M Werner; Michael Chattergoon; Andrea L Cox; Volker Lohmann; Barbara Rehermann Journal: Gastroenterology Date: 2014-03-28 Impact factor: 22.682
Authors: Alexander Hoh; Maximilian Heeg; Yi Ni; Anita Schuch; Benedikt Binder; Nadine Hennecke; Hubert E Blum; Michael Nassal; Ulrike Protzer; Maike Hofmann; Stephan Urban; Robert Thimme Journal: J Virol Date: 2015-05-13 Impact factor: 5.103
Authors: Keisuke Ojiro; Xiaowang Qu; Hyosun Cho; Jang-June Park; Annelise Vuidepot; Nikolai Lissin; Peter E Molloy; Alan Bennett; Bent K Jakobsen; David E Kaplan; James L Riley; Kyong-Mi Chang Journal: J Virol Date: 2017-04-28 Impact factor: 5.103
Authors: J David Stiffler; Minhhuyen Nguyen; Ji A Sohn; Chen Liu; David Kaplan; Christoph Seeger Journal: PLoS One Date: 2009-08-18 Impact factor: 3.240