Interaction of hepatitis C virus with the type I interferon system

Abstract

Hepatitis C virus (HCV) needs to tightly manipulate host defences in order to establish infection. The innate immune response slows down viral replication by activating cytokines such as the type I interferons (IFN-alpha/beta), which trigger the synthesis of antiviral proteins and modulate the adaptive immune system. HCV has therefore developed a number of countermeasures to stay ahead of the IFN system. Here, I will attempt to summarize the current state of research regarding IFN responses against HCV and the viral escape strategies. Particular emphasis will be put on the newly discovered mechanisms HCV employs to avoid the induction of IFN in infected cells.

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.