The Ras/Raf/MEK Pathway Facilitates HCV Replication Via The Attenuation Of Jak-STAT Pathway

Hepatitis C Virus (HCV) is an RNA virus with envelope belonging to the family Flaviviridae. It contains a positive-sense single-stranded RNA genome which is9600nucleotides in length. There are more than170million people currently affected by chronic HCV infection, it is a major cause of chronic liver diseases worldwide, and it often leads to hepatocellular carcinoma. Approximately30%of cancers have constitutive activation of Ras/Raf/MEK pathway, so we want to study whether there is some relationship between HCV replication and this pathway.Current therapy for HCV infected patients is pegylated interferon alpha (PEG-IFN) with ribavirin. IFN alpha induces antiviral effects and promotes the development of immune response. It transduces signals through a well-studied pathway, the Janus tyrosine kinase-signal transducer and activator of transcription pathway (Jak-STAT pathway). After IFN alpha binding to the IFN-receptor IFNAR1and IFNAR2, the STATl and STAT2are phosphorylated and activated. They form a complex named ISGF3with IFN gene regulatory factor-9(IRF-9), and this complex induces many IFN alpha regulated antiviral genes through binding to their IFN-stimulated regulatory elements (ISREs).In this study, we found that activation of Ras/Raf/MEK pathway by V12, a constitutively active form of Ras, leads to an increase on HCV replication, and this effect is made through the attenuation of Jak-STAT pathway. On the other hand, we found that HCV infection causes an increase on the activation of this pathway. According to our results, we got a model of self-regulation for HCV:HCV infection can activate Ras/Raf/MEK pathway, and this pathway, in turn, facilitates HCV replication through the attenuation of Jak-STAT pathway.