Article

The interferon stimulated gene 15 functions as a proviral factor for the hepatitis C virus and as a regulator of the IFN response

Department of Gastroenterology and Hepatology, University Hospital of Essen, Hufelandstr 55, Essen 45122, Germany.
Gut (Impact Factor: 14.66). 08/2010; 59(8):1111-9. DOI: 10.1136/gut.2009.195545
Source: PubMed

ABSTRACT

Non-response to combination therapy by patients with hepatitis C virus (HCV) has previously been associated with a strong hepatic upregulation of interferon stimulated genes (ISGs) including ISG15. Therefore, the aim of this study was to further elucidate the functional role of this molecule.
ISG15 expression was suppressed by siRNAs or enhanced by over-expression in genomic and subgenomic human or murine HCV replicon systems. In addition, ISG15 expression was analysed in liver samples of patients with HCV prior to antiviral therapy and correlated with clinical and virological parameters.
Short- or long-term knockdown of ISG15 expression suppressed HCV replication comparable to IFNs without evidence for the induction of resistant mutations. Triple therapy consisting of ISG15 knockdown, interferon alpha (IFNalpha) and ribavirin led to complete suppression of the HCV NS5A protein, corresponding to 99% suppression of HCV-RNA compared to 75% suppression by IFNalpha and ribavirin only. Combination treatment of ISG15 knockdown and IFN was associated with enhanced and prolonged expression of selected ISGs. Consistent with these in vitro data, high hepatic ISG15 levels correlated with the unfavourable HCV genotype 1, a high hepatic HCV load and a low antiviral response to IFN during the initial phase of treatment.
ISG15 plays an important role in the HCV replication cycle. Therefore, therapies based on the suppression of ISG15 may provide a promising strategy to overcome non-response to standard combination treatment in the future. Furthermore, analysis of ISG15 prior to therapy may be useful to predict short-term and long-term outcome and thus tailor antiviral therapy with pegIFN and ribavirin.

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    • "ISGylation of IRF3 and RIG-I affects their ubiquitination, leading to an increased stability of IRF3 and decreased functionality of RIG-I. This leads to decreased IFN production and increased viral replication (Shi et al., 2010; Broering et al., 2010; Kim et al., 2008). In line with this proviral role, free ISG15 also stabilizes the deISGylase USP18, which binds IFNA2R (IFN alpha 2 receptor) and blocks IFN signaling (Malakhova et al., 2003; Malakhova et al., 2006; Zhang et al., 2015). "
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    • "The data here agree with our previous study that ISG15 exerts an antiviral effect on HCV RNA replication (Jones et al., 2010). There are conflicting reports on the impact of ISG15 and ISGylation on HCV RNA replication: another report supports our findings (Kim & Yoo, 2010), while other studies have presented contrary evidence that ISG15/ISGylation is either pro-viral (Broering et al., 2010; Chen et al., 2010) or does not alter HCV RNA replication in the absence of IFN (Chua et al., 2009). Given the different approaches used by various groups to determine whether ISG15 affects HCV replication, it is difficult to reconcile all available data. "
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    ABSTRACT: Chronic infection of the liver by hepatitis C virus (HCV) induces a range of host factors including interferon-stimulated genes such as ISG15. ISG15 functions as an anti-viral factor that limits virus replication. Previous studies have suggested that ISG15 could influence HCV replication in both a positive and negative manner. In this report, we have determined the effect of ISG15 on HCV RNA replication in two independent cell lines that support viral genome synthesis by inhibiting ISG15 expression through small-interfering RNA, short-hairpin RNA and CRISPR/Cas9 gene knockout approaches. Our results demonstrate that ISG15 impairs HCV RNA replication both in the presence and absence of interferon stimulation, consistent with an antiviral role for ISG15 during HCV infection. ISG15 conjugation to protein substrates typically requires the E3 ligase, HERC5. Our results show that the inhibitory effect of ISG15 on HCV RNA replication does not require its conjugation to substrates by HERC5.
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