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

丙型肝炎病毒对干扰素耐药的病毒决定因素及其与丙型肝炎特异性抗病毒药物广泛耐药的相关性。

• 批准号: 410921131
• 负责人: Dr. Julie Sheldon
• 金额: --
• 依托单位: TWINCORE
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/410921131?language=en
• 关键词: Viral; determinants; hepatitis; virus; resistance

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.

HCV触发肝脏I型和III型IFN的产生以及大量诱导ISG，然而，该病毒能够在大多数患者中建立慢性，这很可能与HCV主动逃避IFN介导的先天免疫和/或IFN触发的效应机制有关。我们最近开发了一种能够在干扰素α存在下以高滴度生长的HCV细胞培养（HCVcc），基于我们之前的结果显示PKR-和eif2α -磷酸化增加，进而增加宿主蛋白关闭，我们假设病毒适应性变化可能下调HCV依赖性干扰素刺激基因的诱导，从而增加病毒耐药性。在这个项目中，我们的目标是确定赋予抗病毒抗性增加的单个病毒适应性变化，研究这些适应性变化对PKR磷酸化的影响以及PKR磷酸化增加对抗病毒抗性的作用，最后研究适应性变化对IFN先天免疫信号的影响。