Hepatitis C Virus Genetic Diversity and Modulation of Innate Immunity

描述（由申请人提供）：丙型肝炎病毒（HCV）是一个主要的公共卫生问题，也是慢性肝病和肝癌的主要原因。标准的HCV治疗选择是有限的，了解病毒-宿主界面调节先天免疫对HCV是必要的，以开发新的治疗方法和限制感染。本实验室的研究表明，HCV RNA通过与位于HCV RNA 3'非翻译区的poly-U/UC结构域结合，被细胞质病原体识别受体RIG-I识别为非自身。此外，我们的研究已经证明，HCV NS 3/4A蛋白酶通过切割RIG-I结合蛋白IPS-1介导宿主先天性抗病毒免疫应答的病毒逃避。最后，HCV基因型和准种之间的大量遗传多样性导致RIG-I信号通路的可变调节，这对先天性和适应性抗病毒免疫应答构成了主要障碍，并且是支持慢性感染和致病结果的关键因素。综上所述，我们的研究将RIG-I信号通路和HCV NS 3/4A蛋白酶作为调节先天免疫和HCV感染结果的主要病毒-宿主界面。该提案的主要目标是确定HCV遗传多样性和先天抗病毒免疫的病毒调节之间的关系。在这项提案中，我们将调查的假设，HCV的激活和抑制RIG-I信号通路调节先天免疫反应对感染，和这些过程中由于HCV基因型和准种多样性的变化可能会影响病毒学和感染的临床相关性。具体而言，我们将（1）确定触发先天免疫信号传导的HCV poly-U/UC基序和RIG-I的特征，（2）评估HCV基因型和病毒准种内poly-U/UC基序的遗传和功能变异，以及（3）分析HCV NS 3/4A遗传多样性并确定来自不同HCV基因型的NS 3/4A切割IPS-1和阻断先天免疫信号传导的能力。这些研究将揭示HCV遗传多样性在先天免疫调节中的作用，从而为旨在限制HCV感染的治疗和疫苗设计策略提供新的见解。 公共卫生相关性：丙型肝炎病毒（HCV）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。全世界约有1.7亿人持续感染HCV，目前的标准治疗仅限于基于干扰素的治疗，仅50%的感染受试者可以清除病毒。目前还没有预防HCV感染的疫苗策略，因此了解病毒-宿主相互作用调节针对HCV的先天免疫对于开发新的治疗方法和限制感染是必要的。

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.