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The interferon stimulated gene 15 functions as a proviral factor for the hepatitis C virus and as a regulator of the IFN response
  1. Ruth Broering1,
  2. Xiaozhen Zhang2,
  3. Shyam Kottilil2,
  4. Martin Trippler1,
  5. Min Jiang1,
  6. Mengji Lu3,
  7. Guido Gerken1,
  8. Joerg F Schlaak1
  1. 1Department of Gastroenterology and Hepatology, University Hospital of Essen, Essen, Germany
  2. 2Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
  3. 3Institute of Virology, University Hospital of Essen, Essen, Germany
  1. Correspondence to Professor J.F. Schlaak, Department of Gastroenterology and Hepatology, University Hospital of Essen, Hufelandstr. 55, Essen 45122, Germany; joerg.schlaak{at}


Background 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.

Methods 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.

Results 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 α (IFNα) and ribavirin led to complete suppression of the HCV NS5A protein, corresponding to 99% suppression of HCV-RNA compared to 75% suppression by IFNα 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.

Conclusions 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.

  • Interferon stimulated gene 15 (ISG15)
  • hepatitis C virus (HCV)
  • interferon (IFN)
  • IFN response
  • small interfering RNA (siRNA)
  • immune response
  • interferon α
  • liver immunology

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  • Funding JFS is supported by the Deutsche Forschungsgemeinschaft (SCHL377/2-4 & 6-2). This research was supported by the Intramural Research Program of the NIH, (National Institute of Allergy and Infectious Diseases). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Ethical Committee University Hospital of Essen.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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