Figure 1.
Hepatitis C virus (HCV) infection and immune response. HCV can induce several signalling pathways. (A) Toll-like receptor (TLR) signalling. Activation of TLR3 leads to the recruitment of IκB kinase (IKK)-related kinases, TANK-binding kinase 1 (TBK1, also known as T2K and NAK) and IKKi (also known as IKKϵ). These kinases, together with adaptors TANK and NAP1, catalyse the phosphorylation of interferon (IFN) regulatory factor-3 (IRF-3). TLR3 engagement also results in the activation of transcription factors AP-1 and nuclear factor-κB (NF-κB). Phosphorylated IRF-3 forms a dimer, translocates into the nuclei, binds to DNA and regulates the expression of IFNβ in collaboration with AP-1 and NF-κB. The HCV NS3-4A serine protease may block the phosphorylation and effector action of IRF-3. (B) Retinoic acid-inducible gene-I (RIG-I)-like RNA helicase signalling. After recognition of viral RNA, RIG-I and also Mda5 (not shown) recruit IFNβ promoter stimulator-1 (IPS-1, also known as MAVS, Cardif and VISA) via CARD–CARD (caspase recruitment domain) interaction. IPS-1 is localised to mitochondria and acts as an adaptor that plays a critical role in the activation of IRF-3 and IRF-7 in a TBK1- and IKKi-dependent manner. IPS-1 also interacts with the Fas-associated death domain protein (FADD), which is required for the activation of IRF-3 and NF-κB. IRF-7 forms a dimer, translocates into the nucleus to induce IFNα/β; homodimers of IRF-3 collaborate with NF-κB to induce IFNβ. IPS-1 is targeted and inactivated by NS3-4A, a serine protease from HCV known to block IFNβ production. (C) IFN signalling. Endogenous IFNα/β bind to a common receptor expressed at the surface of target cells. Receptor engagement leads to the activation of STAT1 (signal transducer and activator of transcription 1) and STAT2, which, together with ISGF3G (IFN-stimulated gene factor 3, γ subunit)/IRF-9, bind to cis-acting IFN-stimulated response elements (ISREs) (D), thereby activating the transcription of IFNα/β-inducible genes such as those encoding RNase L and protein kinase R (PKR) which degrade viral RNAs and block their translation. Also, the HCV core protein has been shown to induce the expression of SOCS3 (suppressor of cytokine signalling 3), which can suppress Jak (Janus kinase)–STAT signalling events and block the IFN-induced formation of ISGF3.58 PAMP, pathogen-associated molecular pattern.