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（由申请人提供）：尽管抗病毒药物开发取得了最新进展，但丙型肝炎病毒（HCV）仍然是慢性肝病和癌症的主要原因，获得治疗的机会有限，耐药性迅速发展，并且没有有效的疫苗。因此，改进治疗和制造疫苗的需求尚未得到满足，因为大多数抗病毒疫苗都会引发针对病毒颗粒的体液反应，因此需要进一步研究以了解 HCV 颗粒的结构和组装，这些颗粒通过抗体中和而免受抗体中和的影响。与血清脂蛋白的尚未表征的相互作用也是了解黄病毒科（临床上重要的病毒病原体的一个大家族）以及更广泛的正链 RNA 病毒的一个有价值的模型系统。正链 RNA 病毒编码的解旋酶有助于病毒组装吗？”该提案建立在我们在上一个资助期间成功检查 HCV 颗粒组装的基础上，这既可以作为病毒结构的独特范式，也可以作为病毒组装的模型系统。通过利用我们之前的成功并采用新方法，我们将实现以下三个目标：1）确定 HCV 解旋酶结构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在深层次上理解病毒解旋酶在包膜正链RNA病毒组装过程中的作用奠定基础。提供对核衣壳组装协调的见解，并首次严格测试 HCV 颗粒结构的流行模型。