Antigenic structures of HCV envelope glycoproteins (Env)

HCV 包膜糖蛋白 (Env) 的抗原结构

• 批准号: 10428300
• 负责人: ROBYN L STANFIELD
• 金额: $ 63.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10428300
• 关键词: Alanine; Animals; Antibodies; Antibody Response; Antigens; Binding; Binding Sites; CD81 gene; Cell Culture Techniques; Cells; Chronic; Complex; Cryoelectron Microscopy; Crystallization; Data; Electron Microscopy; Engineering; Epitope Mapping; Epitopes; Face; Flavivirus; Glycoproteins; Goals; Hepatitis C Vaccine; Hepatitis C virus; Human; Immune; Immune response; Immune system; Immunize; Length; Location; Malignant neoplasm of liver; Maps; Mediating; Membrane Fusion; Methods; Molecular; Molecular Conformation; Monoclonal Antibodies; Negative Staining; Pan Genus; Pathway interactions; Patients; Population; Production; Protein Engineering; Proteins; Public Health; Publishing; Reporting; Research; Resolution; Role; Scanning; Structural Models; Structure; Surface; Surface Antigens; System; Techniques; Testing; Vaccine Antigen; Vaccine Design; Vaccines; Viral; Virion; Virus; Virus Replication; X-Ray Crystallography; base; cell assembly; chronic liver disease; design; env Gene Products; flexibility; improved; neutralizing antibody; next generation; particle; polyclonal antibody; prevent; protein expression; rational design; receptor; spatial relationship; structural biology; vaccine candidate; vaccine trial; virus envelope

PROJECT SUMMARY/ABSTRACT Hepatitis C virus (HCV) chronically infects ~1% of the global population, predisposing patients to chronic liver disease and liver cancer. To control and eventually eradicate this major public health threat, a molecular understanding of the HCV surface antigens is one of highest priorities in HCV research to aid in rational design of effective vaccines. The HCV surface envelope proteins (Env), comprised of heterodimers of the E1 and E2 glycoproteins, are responsible for viral attachment and entry into host cells and for assembly of infectious virus particles. The E1 and E2 glycoproteins are also the main targets of neutralizing antibodies in the immune system. The overall goals of Project 1 of this P01 proposal are to determine high-resolution structures of HCV envelope glycoproteins and engineered vaccine antigens by X-ray crystallography and electron microscopy. The Specific Aims of this project are (1) To determine the antigenic landscape of E1E2 immune epitopes; (2) To determine the structure of E2 in complex with host receptor CD81; and (3) To determine the structure of E1E2 complex. These structures will be critical for understanding the HCV entry mechanism and the immune response at the atomic level which in turn will enable structure-based approaches for rational design and engineering of E1E2-based vaccine candidates in Project 2 of this P01 proposal.

项目总结/摘要 丙型肝炎病毒（HCV）慢性感染约1%的全球人口，使患者易患慢性肝病。 疾病和肝癌。为了控制并最终消除这一重大公共卫生威胁， 对HCV表面抗原的理解是HCV研究的最高优先级之一，以帮助进行合理设计 有效的疫苗。HCV表面包膜蛋白（Env）由E1和E2的异二聚体组成， 糖蛋白，负责病毒附着和进入宿主细胞以及感染性病毒的组装 粒子E1和E2糖蛋白也是免疫系统中中和抗体的主要靶标。 本P01提案项目1的总体目标是确定HCV包膜的高分辨率结构 通过X射线晶体学和电子显微镜观察糖蛋白和工程疫苗抗原。具体 本项目的目的是：（1）确定E1 E2免疫表位的抗原分布;（2） 确定与宿主受体CD 81复合的E2的结构;和（3）确定E2的结构， E1 E2复合体。这些结构对于理解HCV的进入机制和免疫应答是至关重要的。 在原子水平上的响应，这反过来将使基于结构的方法，合理的设计， 本P01提案项目2中基于E1 E2的候选疫苗的工程化。