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

HCV触发肝脏中I型和III型IFN的产生以及ISG的大量诱导，然而，该病毒能够在大多数患者中建立慢性，这最有可能与HCV主动逃避IFN介导的先天免疫和/或IFN触发的效应器机制有关。我们最近开发了一种细胞培养物产生的HCV（HCV 3），其能够在干扰素α存在下以高滴度生长，并且基于我们先前的结果，其显示PKR-和EIF 2 α-磷酸化的增加，进而宿主蛋白质关闭的增加，我们假设病毒适应性变化可能下调干扰素刺激基因的HCV依赖性诱导，这进而赋予增加的病毒抗性。我们的目标是在这个项目中确定个别病毒的适应性变化，赋予增加抗病毒耐药性，研究这些适应性变化的PKR磷酸化的影响和增加的PKR磷酸化的抗病毒耐药性的作用，并最终研究适应性变化对IFN先天免疫信号的影响。

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.