Hepatitis C virus escape from the interferon regulatory factor 3 pathway by a passive and active evasion strategy.
Hepatitis C virus (HCV) has been known to replicate with extremely varying efficiencies in different host cells, even within different populations of a single human hepatoma cell line, termed Huh-7. Several reports have implicated the retinoic-acid inducible gene I (RIG-I)/ interferon regulatory factor 3 (IRF-3) pathway of the innate antiviral response with differences in host cell permissiveness to HCV. To investigate the general impact of the IRF-3 response onto HCV replication in cell culture, we generated an ample array of stable Huh-7 cell lines with altered IRF-3 responsiveness. Neither blocking IRF-3 activation in various host cells by expression of dominant negative RIG-I or HCV NS3/4A protease nor reconstitution of RIG-I signaling in Huh7.5, a cell clone known to be defective in this pathway, had any impact on HCV replication. Only by overexpressing constitutively active RIG-I or the signaling adaptor Cardif (also known as interferon-beta promoter stimulator 1, mitochondrial anti-viral signaling protein, or virus-induced signaling adaptor), both leading to a stimulation of the IRF-3 pathway in the absence of inducers, was HCV replication significantly inhibited. We therefore assessed the extent of RIG-I- dependent IRF-3 activation by different species of RNA, including full-length HCV genomes and HCV RNA duplexes, and observed strong induction only in response to double-stranded RNAs.


CONCLUSIONS
Based on these findings, we propose a refined model of innate immune escape by HCV involving limited initial induction and stringent subsequent control of the IRF-3 response.
Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany.
Marco
M
Binder
Georg
G
Kochs
Ralf
R
Bartenschlager
Volker
V
Lohmann
D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D016174:Hepacivirus / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D012330:RNA, Double-Stranded / Q000502:physiology; D012367:RNA, Viral / Q000502:physiology*; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000502:physiology; D014779:Virus Replication / Q000502:physiology*
D050838:Interferon Regulatory Factor-3; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases