Antigenic structures of HCV envelope glycoproteins (Env)

项目摘要/摘要 丙型肝炎病毒(丙型肝炎病毒)慢性感染全球人口的1%，使患者易患慢性肝病 疾病和肝癌。为了控制并最终根除这种重大的公共卫生威胁，一种分子 了解丙型肝炎病毒表面抗原是丙型肝炎病毒研究的最优先事项之一，以帮助进行合理的设计 有效疫苗的数量。丙型肝炎病毒表面包膜蛋白(Env)，由E1和E2的异源二聚体组成 糖蛋白，负责病毒的附着和进入宿主细胞以及传染性病毒的组装 粒子。E1和E2糖蛋白也是免疫系统中和抗体的主要目标。 本P01提案的项目1的总体目标是确定丙型肝炎病毒包膜的高分辨率结构 用X射线结晶学和电子显微镜研究糖蛋白和工程疫苗抗原。具体的 这项计划的目的是(1)确定E1E2免疫表位的抗原性；(2) 确定E2与宿主受体CD81的复合体的结构；(3)确定 E1E2复合体。这些结构对于了解丙型肝炎病毒的进入机制和免疫力是至关重要的。 原子级别的响应，这将使基于结构的方法能够进行合理的设计和 在本P01提案的项目2中对基于E1E2的候选疫苗进行工程设计。

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.