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 world wide. Alpha interferon (IFN-cw) therapy of chronic hepatitis C leads to a s ustained response in 10 to 20% of patients only. The mechanisms of viral pe rsistence and the pathogenesis of hepatitis C are poorly understood. We est ablished continuous human cell lines, allowing the tightly regulated expres sion of the entire HCV open reading frame under the control of a tetracycli ne-responsive promoter. Using this in vitro system, we analyzed the effect of HCV proteins on IFN-induced intracellular signaling. Expression of HCV p roteins in these cells strongly inhibited IFN-alpha-induced signal transduc tion through the Jak-STAT pathway. Inhibition occurred downstream of STAT t yrosine phosphorylation. Inhibition of the Jak-STAT pathway was not restric ted 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-kappa B was not affected. Interference of HCV with IFN-alpha-induced signaling through the Jak-STAT pathway could contribute to the resistance to IFN-alpha thera py observed in the majority of patients and may represent a general escape strategy of HCV contributing to viral persistence and pathogenesis of chron ic liver disease.