Understanding the molecular mechanism(s) of hepatitis C virus (HCV) induced interferon resistance

Abstract

Hepatitis C virus (HCV) is one of the foremost causes of chronic liver disease affecting over 300 million globally. HCV contains a positive-stranded RNA of ~9600 nt and is surrounded by the 5' and 3'untranslated regions (UTR). The only successful treatment regimen includes interferon (IFN) and ribavirin. Like many other viruses, HCV has also evolved various mechanisms to circumvent the IFN response by blocking (1) downstream signaling actions via STAT1, STAT2, IRF9 and JAK-STAT pathways and (2) repertoire of IFN Stimulatory Genes (ISGs). Several studies have identified complex host demographic and genetic factors as well as viral genetic heterogeneity associated with outcomes of IFN therapy. The genetic predispositions of over 2000 ISGS may render the patients to become resistant, thus identification of such parameters within a subset of population are necessary for management corollary. The ability of various HCV genotypes to diminish IFN antiviral responses plays critical role in the establishment of chronic infection at the acute stage of infection, thus highlighting importance of the resistance in HCV treated groups. The recently defined role of viral protein such as C, E2, NS3/NS4 and NS5A proteins in inducing the IFN resistance are discussed in this article. How the viral and host genetic composition and epistatic connectivity among polymorphic genomic sites synchronizes the evolutionary IFN resistance trend remains under investigation. However, these signals may have the potential to be employed for accurate prediction of therapeutic outcomes. In this review article, we accentuate the significance of host and viral components in IFN resistance with the aim to determine the successful outcome in patients.

Keywords: BOC; CD; DsRNA; ER; GAS; GT; HCV; Hepatitis C virus (HCV); IFN; IFN-stimulated response elements; IFN-α receptor; IFNAR; IL; IR; IRES; IRF3; IRRDR; ISDR; ISG; ISRE; Interferon (IFN); Interferon stimulatory genes (ISGs); NF-κb; PI; PKR; PePHD; Protein kinase R (PKR); RE-1; REST; SNP; SOCS; STAT; SVR; Single nucleotide polymorphism (SNP); Suppressor of cell signaling (SOCS); T-helper; TLR3; TVR; Th; UPR; UTR; boceprevir; cluster of differentiation; double stranded RNA viruses; eIF2α; endoplasmic reticulum; eukaryotic initiation factor 2α; gamma interferon activation site; genotype; hepatitis C virus; insulin resistance; interferon; interferon and ribavirin resistance determining region; interferon regulatory factor 3; interferon sensitivity determining region; interferon stimulatory genes; interleukin; internal ribosome entry site; nuclear factor kappa-light-chain-enhancer of activated B cells; phosphorylation homology domain; protease inhibitor; protein kinase R; repressor element-1; repressor element-1 silencing transcription factor; signal transducer and activator of transcription; single nucleotide polymorphisms; suppressor of cytokine signaling; sustained virological response; telaprevir; toll like receptor 3; unfolded protein response; untranslated regions.