Molecular determinants of hepatitis C virus assembly

丙型肝炎病毒组装的分子决定因素

• 批准号: 9127554
• 负责人: Brett D. Lindenbach
• 金额: $ 41.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127554
• 关键词: Active Sites; Address; Antibodies; Antiviral Agents; Apolipoprotein E; Area; Basic Science; Behavior; Binding Proteins; Biological Models; Complex; Data; Drug resistance; Family; Flaviviridae; Funding; Genetic; Genotype; Glycoproteins; Hepatitis C Vaccine; Hepatitis C virus; High Density Lipoproteins; Hybrids; Infection; Infectious hepatitides; Investments; Learning; Lipoproteins; Low-Density Lipoproteins; Malignant neoplasm of liver; Maps; Mediating; Modeling; Molecular; Mutation; Nonstructural Protein; Nucleocapsid; Phylogenetic Analysis; Process; Public Health; RNA; RNA Binding; RNA Helicase; RNA Viruses; RNA replication; Research; Role; Serum; Structural Models; Structure; System; Testing; Time; Transmembrane Domain; Vaccine Design; Vaccine Therapy; Vaccines; Viral; Viral Core Proteins; Viral Drug Resistance; Viral Structural Proteins; Virion; Virus; Virus Assembly; Virus Replication; chronic liver disease; cost; density; design; drug development; helicase; improved; in vitro activity; in vivo; insight; killings; member; novel; novel strategies; nucleoside triphosphatase; pathogen; public health relevance; response; success; viral RNA; virus host interaction

 DESCRIPTION (provided by applicant): Despite recent advances in antiviral drug development, hepatitis C virus (HCV) remains a major cause of chronic liver disease and cancer, access to therapy is limited, drug resistance evolves rapidly, and there is no effective vaccine. Thus, there is an unmet need to improve therapy and to create a vaccine. As most antiviral vaccines elicit humoral responses against virus particles, further research is needed to understand the structure and assembly of HCV particles, which are protected from antibody neutralization through an as-yet-uncharacterized interaction with serum lipoproteins. HCV is also a valuable model system for understanding the Flaviviridae - a large family of clinically important viral pathogens - as well as positive-strand RNA viruses more generally. A key unanswered question is "how do positive-strand RNA virus-encoded helicases contribute to virus assembly?" This proposal builds upon our success in the previous funding period to examine HCV particle assembly, both as a unique paradigm of virus structure and as a model system for understanding helicase function. By leveraging our prior success and adapting new approaches, we will achieve the following three Aims: 1) establish the role of the HCV helicase domain in virus assembly; (2) define functional interactions within the virus assembly complex; and (3) determine the role of Apolipoprotein E in virus structure. Successful completion of this Project will lay the groundwork for understanding, at a deep mechanistic level, the role of viral helicases during the assembly of enveloped, positive-strand RNA viruses, provide insights into the coordination of nucleocapsid assembly, and - for the first time - rigorously test the prevailing model of HCV particle structure.

 描述（由适用提供）：尽管抗病毒药物开发的最新进展，但乙型肝炎病毒（HCV）仍然是慢性肝病和癌症的主要原因，但获得治疗的途径有限，耐药性迅速发展，并且没有有效的疫苗。由于大多数抗病毒疫苗都会引起针对病毒颗粒的体液反应，因此需要进一步的研究了解HCV颗粒的结构和组装，而HCV颗粒的结构和组装通过与血清脂蛋白的尚未添加的相互作用来保护抗体神经化。 HCV也是一种有价值的模型系统，用于了解Flaviviridae（一个大型临床上重要的病毒病原体）以及阳性链RNA病毒。一个关键的未解决的问题是“阳性链RNA病毒编码的解旋酶如何有助于病毒组装？”该提议建立在我们在上一流的资金期间的成功基础上，既是病毒结构的独特范式又是理解解旋酶功能的模型系统。通过利用我们先前的成功并调整新方法，我们将实现以下三个目标：1）确定HCV解旋酶域在病毒组装中的作用； （2）定义病毒组装复合物中的功能相互作用； （3）确定载脂蛋白E在病毒结构中的作用。该项目的成功完成将为理解深层机械水平的理解，即在包裹的，阳性链RNA病毒组装过程中病毒式解旋酶的作用，为核OCAPSID组装的协调提供了见解，并且 - 首次严格测试了HCV粒子结构的普遍模型。