Interaction of hepatitis C virus with the type I interferon system

Figure 1 Type I IFN gene expression. Detection of viral ssRNA and dsRNA leads to transactivation of IFN-α and IFN-β promotors by IRF-7 and IRF-3. IRF-3 is phosphorylated by the kinases IKKε and TBK-1 which in turn are activated by the intracellular RNA-sensor proteins RIG-I and MDA5. RIG-I preferentially senses 5’triphosphorylated ssRNAs (pppRNA) whereas MDA-5 recognizes dsRNA. Cardif (also termed IPS-1/MAVS/VISA) serves as an adaptor protein connecting RNA sensing and IRF-3 phosphorylation. A second dsRNA signaling pathway involves endosomal TLR-3 and the adaptor protein TRIF which also activates IKKε and TBK-1. The endosomal ssRNA receptor TLR7 utilizes the adaptor protein MyD88 to stimulate IFN-α synthesis via the kinases IRAK4 and IRAK1 and the transcription factor IRF-7.

Figure 2 Cellular response to IFNs. Newly synthesized IFN-α/β binds to its cognate receptor (IFNAR) and activates the expression of numerous IFN-stimulated genes (ISGs) via the JAK/STAT pathway. ADAR, P56, OAS and PKR are IFN-stimulated gene products with antiviral properties against HCV. The SOCS and PIAS proteins negatively regulate the IFN-induced signaling pathway at different stages.