Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway

J Virol. 1999 Oct;73(10):8469-75. doi: 10.1128/JVI.73.10.8469-8475.1999.


Hepatitis C virus (HCV) infection is a leading cause of liver disease worldwide. Alpha interferon (IFN-alpha) therapy of chronic hepatitis C leads to a sustained response in 10 to 20% of patients only. The mechanisms of viral persistence and the pathogenesis of hepatitis C are poorly understood. We established continuous human cell lines, allowing the tightly regulated expression of the entire HCV open reading frame under the control of a tetracycline-responsive promoter. Using this in vitro system, we analyzed the effect of HCV proteins on IFN-induced intracellular signaling. Expression of HCV proteins in these cells strongly inhibited IFN-alpha-induced signal transduction through the Jak-STAT pathway. Inhibition occurred downstream of STAT tyrosine phosphorylation. Inhibition of the Jak-STAT pathway was not restricted to IFN-alpha-induced signaling but was observed in leukemia inhibitory factor-induced signaling through Stat3 as well. By contrast, tumor necrosis factor alpha-induced activation of the transcription factor NF-kappaB was not affected. Interference of HCV with IFN-alpha-induced signaling through the Jak-STAT pathway could contribute to the resistance to IFN-alpha therapy observed in the majority of patients and may represent a general escape strategy of HCV contributing to viral persistence and pathogenesis of chronic liver disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Hepacivirus / physiology*
  • Hepatitis C / drug therapy
  • Hepatitis C / metabolism
  • Hepatitis C / virology*
  • Humans
  • Interferon-alpha / pharmacology
  • Interferon-alpha / therapeutic use
  • NF-kappa B / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • STAT1 Transcription Factor
  • Signal Transduction*
  • Trans-Activators / metabolism
  • Viral Proteins / biosynthesis*
  • Virus Replication


  • Antiviral Agents
  • DNA-Binding Proteins
  • Interferon-alpha
  • NF-kappa B
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • Viral Proteins
  • Protein-Tyrosine Kinases