Viral determinants of hepatitis C virus resistance to interferon and their relevance for broad resistance to HCV specific antivirals.

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HCV triggers type I and type III IFN production in the liver as well as massive induction of ISG, however, the virus is able to establish chronicity in most patients, this is most likely linked to HCV’s active evasion from IFN-mediated innate immunity and/or IFN-triggered effector mechanisms. We have recently developed a cell culture produced HCV (HCVcc) able to grow at high titres in the presence of interferon alpha and based on our previous results that show an increase in PKR- and EIF2alpha- phosphorylation and in turn an increase in host protein shut down, we hypothesize that viral adaptive changes may down-regulate HCV-dependent induction of interferon stimulated genes which in turn confers increased viral resistance. We aim in this project identify individual viral adaptive changes that confer increased antiviral resistance, investigate the impact of these adaptive changes on PKR phosphorylation and the role of increased PKR phosphorylation for antiviral resistance and finally investigate the impact of adaptive changes on IFN innate immune signalling.