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: 8660597
• 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/8660597
• 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; 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.

描述（由申请人提供）：这些研究的长期目标是确定丙型肝炎病毒（HCV）感染期间发生的先天宿主-病毒相互作用，希望这将导致这种疾病的新治疗方法。HCV是一种非致细胞病变的正链RNA病毒，可引起急性和慢性肝炎以及肝细胞癌。在美国约有2-4百万人慢性感染HCV，全世界有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。最近开发的一个强大的细胞培养模型的HCV感染允许分析整个HCV的生命周期，并有利于分析宿主-病毒的相互作用，决定HCV感染的结果。使用该模型，我们最近报道了HCV不会诱导感染细胞中的1型干扰素或干扰素刺激基因;病毒NS 3/4A蛋白酶通过切割dsRNA信号传导途径中的关键中间体来阻断双链（ds）RNA信号传导;并且HCV通过由HCV NS 4 B蛋白介导的完全新的NS 3/4A非依赖性机制来逃避感染细胞中的先天宿主应答。我们还发现，1型干扰素快速调节细胞microRNA（miRNA）的表达，部分介导IFN抗HCV的抗病毒作用。这些发现确定了一个以前未被怀疑的干扰素反应的效应臂，有助于控制HCV感染。在本提案中，我们将扩展这些研究，具体目标如下。在具体目标1中，我们将通过确定NS 4 B是否直接与RIG-I相互作用、是否调节RIG-I亚细胞定位以及是否阻断RIG-I结合dsRNA的能力来表征NS 4 B阻断双链RNA信号传导的分子机制。在特定目标2中，我们将鉴定介导干扰素抗HCV抗病毒作用的细胞miRNA库，鉴定介导其抗病毒作用的细胞基因，并表征这些基因控制HCV感染的机制。总的来说，这些实验将提供深入了解病毒逃避和宿主防御机制，可能导致新的抗病毒策略的发展，以终止慢性HCV感染。

项目成果

An integrated transcriptomic and meta-analysis of hepatoma cells reveals factors that influence susceptibility to HCV infection.

• DOI: 10.1371/journal.pone.0025584
• 发表时间: 2011
• 期刊: PloS one
• 影响因子: 3.7
• 作者: MacPherson JI;Sidders B;Wieland S;Zhong J;Targett-Adams P;Lohmann V;Backes P;Delpuech-Adams O;Chisari F;Lewis M;Parkinson T;Robertson DL
• 通讯作者: Robertson DL