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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

基本信息

批准号：
7916956
负责人：
FRANCIS VINCENT CHISARI
金额：
$ 47.48万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-12 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7916956
关键词：
Acute Animal Model Antiviral Agents Biochemical Carcinoma Cell Culture Techniques Cell Line Cells Chronic Hepatitis Chronic Hepatitis C Cleaved cell Complement Defense Mechanisms Development Disease Double-Stranded RNA Genes Genome Genotype Goals Hepatitis C Hepatitis C virus Hepatocyte Human Immune response Infection Interferons Investigation Knowledge Lead Life Cycle Stages Liver Liver Failure Mediating MicroRNAs Microarray Analysis Modeling Molecular Molecular Cloning Outcome Peptide Hydrolases Persons Primary carcinoma of the liver cells Proteins RNA Viruses Reporting Research Series Signal Pathway Signal Transduction Signaling Molecule System Therapeutic Upper arm Viral Viral Proteins Virus Virus Replication base cellular targeting hepatoma cell insight novel novel therapeutic intervention pathogen promoter research study response virus development virus host interaction

项目摘要

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 hepatocelluar 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 have recently shown that that the viral NS3/4A protease blocks double stranded (ds) RNA signaling and type 1 interferon (IFN) induction by cleaving a key intermediate in the dsRNA signaling pathway, and we discovered an entirely novel NS3/4A-independent mechanism whereby HCV evades the innate host response in infected cells. We also discovered that IFN rapidly modulates the expression of numerous cellular microRNAs (miRs) several of which have sequence-predicted targets within the HCV genome, that synthetic miR-mimics corresponding to several of these IFN-induced miRs reproduces the antiviral effects of IFN on HCV infection, and that neutralization of these miRs significantly reduces the antiviral effects of IFN against HCV. Finally, we showed that IFN inhibits the expression of the liver-specific miR-122 which is known to be essential for HCV replication. These findings identify a previously unsuspected effector arm of the innate host response that contributes to the control of HCV infection. In Specific Aim 1, we will use molecular and biochemical approaches to define the viral protein(s) that mediate NS3/4A-independent suppression of dsRNA-induced IFN expression (subaim 1a), identify the cellular dsRNA signaling molecule that is targeted by that (those) protein(s) (subaim 1b), and determine the molecular basis of this novel host evasion mechanism (subaim 1c). These results will enrich our understanding of the basis for viral persistence in HCV infection and, potentially, identify a previously unappreciated target(s) in HCV for the development of antiviral drugs. In Specific Aim 2, we will use microarray technology to define the full complement of cellular microRNAs that are regulated by type 1 and type 2 interferons in human liver cells (subaim 2a); determine whether any of these IFN-regulated miRs inhibit HCV infection (subaim 2b) and mediate IFN¿s antiviral effects (subaim 2c); and identify the viral and cellular targets of these miRs (subaim 2d), and the step(s) in the virus life cycle they interrupt when they inhibit HCV infection (subaim 2e). Collectively, these experiments will provide insight into an entirely new innate defense mechanism that protects the host against HCV infection and, potentially, lead to the development of novel antiviral strategies that exploit this mechanism to terminate chronic HCV infection.

这些研究的长期目标是确定在丙型肝炎期间发生的先天宿主-病毒相互作用