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Hepatitis C virus genome structure: dynamic roles in replication and infectivity

丙型肝炎病毒基因组结构：复制和感染性中的动态作用

基本信息

批准号：
9980781
负责人：
Brett D. Lindenbach
金额：
$ 55.3万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980781
关键词：
Animals Antiviral Agents Architecture Behavior Binding Biochemical Biochemistry Biological Models Cells Communities Complement Complex Crystallography Dengue Virus Disease Elements Enzymatic Biochemistry Event Funding Future Genetic Genome Health Hepatitis C virus Human In Vitro Individual Infection Integration Host Factors Knowledge Light Malignant neoplasm of liver Maps Methods Molecular Monitor Nonstructural Protein Phase Play Population Process Proteins Public Health RNA RNA Binding RNA Biochemistry RNA Viruses RNA replication RNA-Protein Interaction Reagent Regulation Replication Initiation Research Research Project Grants Role Rubber Site Specificity Structure Technology Testing Therapeutic Translating United States Untranslated RNA Viral Viral Genome Viral Nonstructural Proteins Viral Physiology Viral Proteins Virus Virus Assembly Virus Replication Work chronic liver disease combat crosslink design genetic approach genomic RNA helicase improved in vivo innovation insight interdisciplinary approach novel strategies protein complex protein function recruit replicase structural biology success tool viral RNA virology virus genetics

项目摘要

Project Summary Hepatitis C virus (HCV) infects a large population within the United States (~2%), where it remains a major cause of chronic liver disease and cancer. While potent antiviral drugs have recently become available, long-term success in combating HCV-related disease requires a clear understanding of viral replication mechanisms. Furthermore, HCV provides an essential model system for understanding the replication of many related positive-strand RNA viruses, including dengue virus and other unmet threats to human and animal health. To date, most work on HCV replication has focused on activities of the viral nonstructural (NS) proteins or the role of host factors in this process. Very little has been done on role of the HCV RNA genome in replication or on the functional interactions between the viral genome and NS proteins. This is a critical gap, since the interaction between HCV RNA and viral proteins is literally where the “rubber hits the road”, and the key events in viral replication occur. We will leverage our recent success in defining molecular networks among the NS proteins, and in characterizing RNA and RNA-protein complexes, and we will exploit new approaches for monitoring RNA interactions in vivo in order to achieve the following three aims: (A) Determine the functional RNA structures within the HCV genome; (B) Define the molecular interactions between NS proteins and the RNA genome, establishing their interaction sites and functional relevance during sequential phases of the viral lifecycle; (C) Define the structural features and functional attributes of the Replication Pre-initiation Complexes (RPIC), which initiates the entire process of virus propagation. These objectives will be accomplished by integrating innovative approaches for studying viral genetics, RNA crosslinking and sequencing, enzymology and crystallography, and capitalizing on our respective strengths in virology and RNA biochemistry. By focusing on the molecular interplay between genomic RNA and NS proteins, the work is conceptually innovative. In developing the tools needed to advance this research, the project is also technologically innovative, resulting in methods and reagents that will be of widespread utility to the RNA virus research community.

项目总结