Innate Control of Hepatitis C Virus Infection: Antiviral and Evasion Mechanisms

丙型肝炎病毒感染的先天控制：抗病毒和逃避机制

• 批准号: 8279181
• 负责人: FRANCIS VINCENT CHISARI
• 金额: $ 47万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279181
• 关键词: Acute Hepatitis; Animal Model; Antiviral Agents; Binding; Biology; Cell Culture Techniques; Cells; Chronic Hepatitis; Chronic Hepatitis C; Cleaved cell; Development; Disease; Double-Stranded RNA; Genes; Genotype; Goals; Hepatitis C; Hepatitis C virus; Host Defense Mechanism; Human; Immune response; Infection; Interferons; Investigation; Lead; Life; Life Cycle Stages; Liver Cirrhosis; Liver Failure; Malignant neoplasm of liver; Mediating; Mediator of activation protein; MicroRNAs; Modeling; Molecular; Molecular Cloning; Outcome; Patients; Peptide Hydrolases; Persons; Primary carcinoma of the liver cells; Proteins; Public Health; RNA Viruses; Reporting; Research; Signal Pathway; Signal Transduction; System; United States; Viral; Virus; Work; arm; base; improved; insight; novel; novel therapeutic intervention; public health relevance; research study; response; socioeconomics; virus host interaction

DESCRIPTION (provided by applicant): The long term goal of these studies is to define the innate host-virus interactions that occur during hepatitis C virus (HCV) infection with the hope that this will lead to novel therapeutic approaches to this disease. HCV is a noncytopathic, positive-strand RNA virus that causes acute and chronic hepatitis and hepatocellular carcinoma. Approximately 2-4 million persons are chronically infected by HCV in the USA and 170 million people are chronically infected worldwide, many of whom will die from liver failure and hepatocellular carcinoma. The recent development of a robust cell culture model of HCV infection permits analysis of the entire HCV life cycle and facilitates analysis of the host-virus interactions that determine the outcome of HCV infection. Using that model we recently reported that HCV doesn't induce type 1 interferon or interferon stimulated genes in infected cells; that the viral NS3/4A protease blocks double stranded (ds) RNA signaling by cleaving a key intermediate in the dsRNA signaling pathway; and that HCV evades the innate host response in infected cells by an entirely novel NS3/4A-independent mechanism that is mediated by the HCV NS4B protein. We also discovered that type 1 interferon rapidly modulates the expression of a subset of cellular microRNAs (miRNAs) that partially mediate the antiviral effects of IFN against HCV. These findings identify a previously unsuspected effector arm of the interferon response that contributes to the control of HCV infection. In the current proposal we will extend these studies with the following Specific Aims. In Specific Aim 1, we will characterize the molecular mechanism whereby NS4B blocks double stranded RNA-signaling by determining if it directly interacts with RIG-I, if it regulates RIG-I subcellular localization, and if it blocks the ability of RIG-I to bind dsRNA. In Specific Aim 2, we will identify the repertoire of cellular miRNAs that mediate the antiviral effect of interferon against HCV, identify the cellular genes that mediate their antiviral effects, and characterize the mechanism whereby those genes control HCV infection. Collectively, these experiments will provide insight into viral evasion and host defense mechanisms that could lead to the development of novel antiviral strategies to terminate chronic HCV infection. PUBLIC HEALTH RELEVANCE: Over 170 million people throughout the world are chronically infected by HCV, 2-4 million of whom live in the United States. Twenty percent of these patients will develop cirrhosis of the liver and about 5% will die from liver failure and cancer. The work described in this proposal will improve our understanding of the biology of this virus with the hope that we will identify vulnerabilities in its life cycle that can be exploited to develop safe and effective antiviral drugs to alleviate the human suffering and socioeconomic burden of this worldwide threat to public health.

描述(申请人提供)：这些研究的长期目标是确定在丙型肝炎病毒(丙型肝炎病毒)感染期间发生的先天宿主-病毒相互作用，希望这将导致对这种疾病的新的治疗方法。丙型肝炎病毒是一种非细胞病变的正链RNA病毒，可引起急性和慢性肝炎和肝细胞癌。美国约有200-400万人慢性感染丙型肝炎病毒，全球有1.7亿人慢性感染，其中许多人将死于肝功能衰竭和肝细胞癌。最近发展的一个强大的丙型肝炎病毒感染细胞培养模型允许分析整个丙型肝炎病毒生命周期，并有助于分析决定丙型肝炎病毒感染结局的宿主-病毒相互作用。利用该模型，我们最近报道，丙型肝炎病毒不会在感染细胞中诱导1型干扰素或干扰素刺激基因；病毒NS3/4A蛋白酶通过切割dsRNA信号通路中的关键中间体来阻止双链(Ds)RNA信号传递；以及丙型肝炎病毒通过一种全新的非NS3/4A独立机制在感染细胞中逃避先天宿主反应，该机制由丙型肝炎病毒NS4B蛋白介导。我们还发现，1型干扰素可以快速调节部分介导干扰素抗丙型肝炎病毒作用的细胞microRNAs(MiRNAs)的表达。这些发现确定了干扰素反应的一个先前未被怀疑的效应臂，它有助于控制丙型肝炎病毒感染。在目前的提案中，我们将扩展这些研究，以实现以下具体目标。在特定的目标1中，我们将通过确定NS4B是否直接与RIG-I相互作用，是否调节RIG-I的亚细胞定位，以及是否阻止RIG-I结合dsRNA的能力，来表征NS4B阻断双链RNA信号的分子机制。在特定的目标2中，我们将确定介导干扰素抗丙型肝炎病毒作用的细胞miRNAs的谱系，确定介导其抗病毒作用的细胞基因，并表征这些基因控制丙型肝炎病毒感染的机制。总的来说，这些实验将提供对病毒逃避和宿主防御机制的洞察，这些机制可能导致开发新的抗病毒策略来终止慢性丙型肝炎病毒感染。 与公共卫生相关：全世界有超过1.7亿人慢性感染丙型肝炎病毒，其中200-400万人生活在美国。其中20%的患者将发展为肝硬变，约5%的患者将死于肝功能衰竭和癌症。这项提案中描述的工作将提高我们对这种病毒生物学的理解，希望我们将找出其生命周期中可被利用的弱点，以开发安全有效的抗病毒药物，以减轻这一全球范围内对公共卫生的威胁所造成的人类痛苦和社会经济负担。