Hepatitis C Virus Genetic Diversity and Modulation of Innate Immunity

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)是一个主要的公共卫生问题，是慢性肝病和肝癌的主要原因。标准的丙型肝炎病毒治疗选择是有限的，了解调节针对丙型肝炎病毒的天然免疫的病毒-宿主界面对于开发新的治疗方法和限制感染是必要的。我们实验室的研究表明，丙型肝炎病毒RNA是通过与位于丙型肝炎病毒RNA 3‘非翻译区的多聚U/UC结构域结合而被细胞质病原体识别受体RIG-I识别为非自我的。此外，我们的研究表明，丙型肝炎病毒NS3/4A蛋白酶通过裂解RIG-I结合蛋白IPS-1来介导病毒逃避宿主的先天抗病毒免疫反应。最后，丙型肝炎病毒基因分型和准物种之间的巨大遗传差异导致RIG-I信号通路的可变调节，这是先天和获得性抗病毒免疫反应的主要障碍，也是导致慢性感染和致病结局的关键因素。综上所述，我们的研究将RIG-I信号通路和丙型肝炎病毒NS3/4A蛋白水解酶联系起来，作为调节先天性免疫和丙型肝炎病毒感染结局的主要病毒-宿主界面。这项建议的主要目的是确定丙型肝炎病毒基因多样性和病毒调节先天抗病毒免疫之间的关系。在这个方案中，我们将研究一种假设，即丙型肝炎病毒激活和抑制RIG-I信号通路调节针对感染的先天免疫反应，这些过程中由于丙型肝炎病毒基因型和准种多样性而产生的变化可能影响感染的病毒学和临床相关性。具体地说，我们将(1)确定触发天然免疫信号的丙型肝炎病毒多聚U/UC基序和RIG-I的特征，(2)评估多聚U/UC基序在不同丙型肝炎病毒基因型和准种内的遗传和功能差异，以及(3)分析丙型肝炎病毒NS3/4A的遗传多样性，并确定不同丙型肝炎病毒的NS3/4A裂解IPS-1和阻断天然免疫信号的能力。拟议的研究将揭示丙型肝炎病毒基因多样性在调节先天免疫中的作用，从而为旨在限制丙型肝炎病毒感染的治疗和疫苗设计策略提供新的见解。 与公共卫生相关：丙型肝炎病毒(丙型肝炎病毒)是一个主要的公共卫生问题，也是全球慢性肝病和肝癌的主要原因。全球约有1.7亿人持续感染丙型肝炎病毒，目前的标准治疗仅限于基于干扰素的治疗，导致只有50%的感染者病毒被清除。目前还没有预防丙型肝炎病毒感染的疫苗策略，因此了解病毒与宿主之间的相互作用调节对丙型肝炎病毒的天然免疫是必要的，以开发新的治疗方法和限制感染。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) is a major public health concern and a leading cause of chronic liver disease and liver cancer. Standard HCV treatment options are limited, and understanding the virus-host interface regulating innate immunity against HCV is necessary to develop new therapies and restrict infection. Studies in our laboratory have revealed that HCV RNA is recognized as non-self by RIG-I, a cytoplasmic pathogen recognition receptor, through binding of the poly-U/UC domain located in the 3' non-translated region of the HCV RNA. In addition, our studies have demonstrated that the HCV NS3/4A protease mediates viral evasion of the host innate antiviral immune response through cleavage of the RIG-I binding protein IPS-1. Finally, substantial genetic diversity between HCV genotypes and quasi-species results in variable regulation of the RIG-I signaling pathway, presenting a major obstacle for innate and adaptive antiviral immune responses, and is a key factor supporting chronic infection and pathogenic outcome. Taken together, our studies connect the RIG-I signaling pathway and the HCV NS3/4A protease as a major virus-host interface regulating innate immunity and HCV infection outcome. The main goal of this proposal is to define the relationship between HCV genetic diversity and viral regulation of innate antivira immunity. In this proposal, we will investigate the hypothesis that HCV activation and suppression of the RIG-I signaling pathway regulates the innate immune response against infection, and variation within these processes due to HCV genotype and quasispecies diversity may affect the virologic and clinical correlates of infection. Specifically, we will (1) identify features of the HCV poly-U/UC motif and RIG-I that trigger innate immune signaling, (2) assess genetic and functional variation in the poly-U/UC motif among HCV genotypes and within the viral quasispecies, and (3) analyze HCV NS3/4A genetic diversity and determine the ability of NS3/4A from different HCV genotypes to cleave IPS-1 and block innate immune signaling. The proposed studies will reveal the role of HCV genetic diversity in the regulation of innate immunity, thus providing new insights for therapeutic and vaccine design strategies aimed at restricting HCV infection. PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV) is a major public health concern and a leading cause of chronic liver disease and liver cancer worldwide. Approximately 170 million people worldwide are persistently infected with HCV, and standard treatment is currently limited to interferon-based therapies that result in viral clearance in only 50% of infected subjects. Vaccine strategies are not currently available for preventing HCV infection, so understanding the virus-host interactions regulating innate immunity against HCV is necessary in order to develop new therapies and restrict infection.