Figure 1. Induction and Evasion of Innate Antiviral Responses by HCV.

HCV RNA structures are detected by cellular RNA sensors. In hepatocytes (left), RIGI and MDA5 recognize 5’ triphosphate RNA, dsRNA, and the long noncoding RNA lncITPRIP-1, respectively, to activate adaptor protein MAVS. MAVS recruits and activates TBK1-regulated phosphorylation of transcription factors IRF3 and NF-κb, resulting in NAP1L1-mediated nuclear translocation and production of type I interferons (IFNB) and type III interferons (IFNL). RIGI and MDA5 signaling are antagonized by HCV proteins (shown in red). HCV NS3 sequesters TBK1; HCV NS5A promotes degradation of NAP1L1; and HCV NS3/4 cleaves ring finger protein 135 (RNF135 or Riplet) and MAVS to prevent IFN expression. Endosomal TLR3 recognizes HCV dsRNA and signals through the adaptor protein TRIF to activate IRF3 hepatoma cell culture experiments. It is not clear whether endocytic uptake of cytoplasmic dsRNA occurs in hepatocytes of HCV-infected livers. HCV NS3/4A cleaves TRIF, impeding IFN signaling. HCV IRES and dsRNA bind PKR to promote or reduce its activity. HCV NS5A stimulates PKR to inhibit translation in immune cells, reducing expression of IFNs. Secreted IFNB and IFNL bind to their respective receptors IFNAR1, IFNAR2, and IFNLR1, IL10RB, expressed on hepatocytes and immune cells (right) to activate JAKs to phosphorylate STAT proteins. STATs form complexes with IRF9 and translocate to the nucleus, where they induce expression of ISGs, which amplify the IFN-mediated, antiviral immune response. HCV core upregulates SOCS3 (an inhibitor of JAK2) and the HCV NS5A protein suppresses STAT1 phosphorylation to impede expression of ISGs. Abbreviations are as follows: TBK1, TANK binding kinase 1; NAP1L1, nucleosome assembly protein 1 like 1; JAK1, Janus kinase 1; STAT, signal transducer and activator of transcription 1; SOCS3, suppressor of cytokine signaling 3; IRF9, interferon regulatory factor 9.