鉴于IFN在抗HCV治疗中的核心地位及HCV核心蛋白变异致干扰素应答抵抗的事实，本项目拟重点探讨核心蛋白位点/结构变异致IFN应答抵抗的机制，在SVR、无应答、复发的三个CHC患者队列中，通过克隆测序及软件预测分析CHC患者HCV核心蛋白准种和移码编码现象；通过基因定向修饰或平行置换的方法制造突变体及嵌合复制子定位核心蛋白致IFN应答抵抗的位点；通过芯片、质谱和电镜技术探讨核心蛋白变异致IFN应答抵抗的分子机制。验证假设：HCV核心蛋白存在一组影响IFN应答的功能位点，通过①自发突变产生相互竞争的F蛋白与核心蛋白准种；或②在脂质微环境中发生可逆的翻译后修饰及③空间结构改变，共同效应通路是影响其与IFN通路中抗病毒效应分子的相互作用，使个体之间、同一个体治疗前后出现有差别的应答反应。为开发IFN应答敏感性的预测模型并最终用于CHC患者治疗前的个体化测评、指导再治疗决策提供依据。

In consideration of the critical role of IFN in treatment for chronic hepatitis C (CHC) and the fact that mutations of HCV core protein relate to IFN resistance. The project aims to focus on the mechanisms of HCV core protein site/struction mutation induced IFN resistance in three groups (SVR group,no-response group,relapse group). The analysis of HCV core protein quasispecies and frameshift coding phenomenon in CHC patients will be carryied out by clone sequencing and software prediction. The locating suspicious sites in core protein that lead to IFN resistance by generating mutations and chimeric replicon though gene directional modification and Parallel displacement, variant-core-protein transfer into cells, use technologies of expression profile chip, mass spectroscopy and electron microscopy to investigate the molecular mechanism of core protein induced IFN resistance. We hope to identify the hypothesis that functional sites which affect IFN response existing in HCV core protein, and further validate mutation of these sites resist to IFN response by the following three ways: generating quasispecies of F protein and core protein by spontaneous mutation, which two proteins compete with each other; reversible posttranslational modification happened in lipid microenvironment; change of space structure of HCV core protein. The common effect pathways are response reactions that influence the interac groups(SVR group,no-response group, relapse group), through clone sequencing and software prediction analysis of HCV core protein quasispecies and drift coding phenomenon in CHC patients, and locating suspicious sites in core protein that lead to IFN resistance by generating mutations and chimeric replicon though gene directional modification and parallel displacement, then investigate the molecular mechanism of core protein induced IFN resistance. we hope to test the hypothesis that functional sites that affect IFN response exist in HCV core protein, and further validate these sites affect IFN response by the following three ways: generating quasispecies that producing F protein and core protein(two proteins that compete with each other) by spontaneous mutation; reversible posttranslational modification happened in lipid microenvironment; change of space structure of HCV core protein. Then they influent the interaction between core functional sites and anti-viral effector molecules in IFN response pathway, leading to various response to IFN between individuals or before and after treatment in one case. Finally, a prediction model for the sensitivity of IFN response will be set up, and it will be applied as an individual assessment before therapy for CHC patients.