(A) Hepatocytes sense HCV dsRNA structures via pattern recognition receptors RIG-I and TLR3. These receptors activate via their adaptor molecules IPS-1 and TRIF, respectively, NF-κB, and the downstream kinases IKKε and TNF receptor–associated factor family member–associated NF-κB activator–binding kinase–1 (TBK1). IKKε and TBK1 phosphorylate the transcription factor IRF3, which dimerizes, translocates to the nucleus, and activates IFN-β gene transcription in synergy with NF-κB. HCV NS3/4A cleaves the adapter molecules TRIF and IPS-1, thereby blocking TLR3 and RIG-I signaling. (B) Binding of IFN-β to the IFN-α/β receptor (IFNAR-1 and -2) activates the JAK/STAT pathway. Specifically, TYK2 and JAK1 kinase activation results in the generation, phosphorylation, and assembly of the trimeric ISGF3 transcription factor complex, which consists of a STAT1–STAT2 heterodimer and IRF9. This complex translocates to the nucleus, binds to IFN-stimulated response elements (ISREs) within the promoter/enhancer region of ISGs and induces 2′-5′ OAS, PKR, and IRF7 production. HCV core interferes with the JAK/STAT pathway by inducing SOCS1/3 and by inhibiting STAT1 phosphorylation. The HCV polyprotein induces protein phosphatase 2A (PP2A), which interferes with STAT1 methylation, thereby increasing the binding of STAT1 to protein inhibitor of activated STAT1 (PIAS). STAT1/PIAS interaction impairs the binding of the ISGF3 complex to the IFN-stimulated response element and blocks the transcription of ISGs. HCV E2 and HCV NS5A inhibit the function of several ISGs (see text for details).