Antigenic structures of HCV envelope glycoproteins (Env)

项目概要/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。

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.