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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.

项目概要丙型肝炎病毒 (HCV) 在美国感染大量人口 (~2%)，在美国仍然是丙型肝炎病毒 (HCV) 的主要感染者。慢性肝病和癌症的主要原因。虽然有效的抗病毒药物最近已成为对抗 HCV 相关疾病的长期成功需要对病毒有清晰的了解复制机制。此外，HCV 提供了一个重要的模型系统来理解许多相关正链RNA病毒的复制，包括登革热病毒和其他未满足的病毒对人类和动物健康的威胁。迄今为止，大多数关于 HCV 复制的工作都集中在活动上病毒非结构（NS）蛋白或宿主因素在此过程中的作用。已经很少了研究HCV RNA基因组在复制中的作用或病毒之间的功能相互作用基因组和 NS 蛋白。这是一个关键的差距，因为 HCV RNA 和病毒之间的相互作用蛋白质实际上是“橡胶上路”的地方，也是病毒复制中关键事件发生的地方。我们将利用我们最近在定义 NS 蛋白之间的分子网络方面的成功，以及表征 RNA 和 RNA-蛋白质复合物，我们将开发新的监测方法 RNA在体内相互作用以达到以下三个目的：（A）确定功能 HCV基因组内的RNA结构； (B) 定义 NS 蛋白之间的分子相互作用和 RNA 基因组，在顺序过程中建立它们的相互作用位点和功能相关性病毒生命周期的各个阶段； (C) 定义结构特征和功能属性复制预启动复合体 (RPIC)，启动病毒传播的整个过程。这些目标将通过整合研究病毒的创新方法来实现遗传学、RNA 交联和测序、酶学和晶体学，并利用我们的在病毒学和RNA生物化学方面各自具有优势。通过关注分子相互作用这项工作在基因组 RNA 和 NS 蛋白之间具有创新性。在开发工具时为了推进这项研究，该项目在技术上也具有创新性，产生了方法以及对 RNA 病毒研究界具有广泛用途的试剂。