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Hepatitis C virus (HCV) infection is among the leading causes of chronic liver disease, with ∼170 million chronically infected worldwide.1–3 The standard of care, consisting of the combination of pegylated interferon (PEG-IFN) plus ribavirin, only induces a sustained virological response (SVR) in half of genotype 1-infected patients. Recent breakthroughs have been reported by the use of protease and polymerase inhibitors.4 5 However, in the near future in HCV treatment, it is likely that PEG-IFN will remain the backbone of treatment since it is needed to prevent HCV resistance and subsequently increase SVR rates.4–6 10 Thus, it is of major importance to understand the IFN pathway and mechanisms of non-response, in order to overcome it and to identify predictive factors of response.
Endogenous type I IFNs are major antiviral cytokines. HCV infection may activate host signalling pathways that induce type I IFNs.7–10 Activation of the Toll-like receptor 3 (TLR3) pathway by double-stranded RNA (dsRNA), generated during HCV infection, leads to phosphorylation of IFN regulatory factor-3 (IRF-3) and activation of transcription factors AP-1 and nuclear factor-κB (NF-κB). IRF-7 and IRF-3 form homodimers and heterodimers, and activate IFNα/β, in collaboration with NF-κB. Then, IFN-α/β binds to a common receptor expressed at the surface of the target cell. Receptor engagement causes the activation of JAK–STAT (Janus kinase/signal transducers and activators of transcription) signalling which, together with ISGF3G/IRF-9, binds to IFN-stimulated response elements (ISREs), thereby activating the transcription of IFNα/β-inducible genes. This results in the production of effector molecules (IFN-stimulated genes), such as RnaseL, and protein kinase R (PKR), that will limit HCV replication.
In a study comparing chronic hepatitis C with histologically normal liver, it has been shown that the most noteworthy changes in hepatic gene expression mainly affected the transcriptional network regulated by IFNs. This includes both IFNα/β-stimulated genes …
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