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. Conclusion: 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. (HEPATOLOGY 2007.)