Inhibition of STAT Pathway Impairs Anti Hepatitis C Virus Effect of Interferon Alpha

Background/Aims: Signal transducer and activator of transcription (STAT) pathway plays an important role in antiviral efficacy of interferon alpha (IFN-alpha). IFN-alpha is the main therapeutic against hepatitis C virus (HCV) infection. We explored effects of IFN-alpha on HCV replication and antiviral gene expression by targeting STAT. Methods: In response to IFN-alpha, STAT status, HCV replication, and antiviral gene expression were analyzed in human hepatoma Huh7.5.1 cells before and after cell culture-derived HCV infection. Results: IFN-alpha treatment induced expression and phosphorylation of STAT1 and STAT2 in Huh7.5.1 cells. Pretreatment of Huh7.5.1 cells with a mAb to IFN alpha receptor (TENAR) 2 decreased TEN-alpha-dependent phosphorylation of STAT1 and STAT2, whereas pretreatment with an IFNAR1 mAb increased such phosphorylation, suggesting that IFNAR mediates IFN-alpha-triggered STAT signaling. During HCV infection, STAT1 and STAT2 phosphorylation could be rescued by IFN-alpha and IFN a-induced phosphorylation of STAT1 and STAT2 was impaired. Inhibition of STAT pathway by Jak inhibitor I significantly enhanced HCV RNA replication and viral protein expression. Antiviral genes coding for IFN regulatory factor 9 and IFN-stimulated gene 15 were up regulated by IFN a during HCV infection but such up-regulation was abrogated by Jak inhibitor I. Conclusion: These results establish that activation of STAT pathway is essential for anti-HCV efficacy of IFN-a. Impairment of IFN-alpha-triggered STAT signaling by HCV may account for evading IFN-a response. (C) 2016 The Author(s) Published by S. Karger AG, Basel