Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway.
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.
Heim
M H
MH
Department of Research, University Hospital Basel, CH-4031 Basel, Switzerland.
Moradpour
D
D
Blum
H E
HE
D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy / Q000378:metabolism / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D016328:NF-kappa B / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014764:Viral Proteins / Q000096:biosynthesis*; D014779:Virus Replication
D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014764:Viral Proteins; D011505:Protein-Tyrosine Kinases