Mechanism of Herpes Simplex Virus (HSV) Induced Membrane Fusion

疱疹病毒与人类宿主中的各种疾病有关，从无症状的到 感染危及生命的疾病，包括脑炎和癌症。除了扮演直接角色之外 癌症的发生，疱疹病毒会增加癌症患者的风险，他们可能会发展为虚弱和生命- 威胁到疱疹病毒感染。生殖器单纯疱疹病毒(HSV)损害，即使临床上不明显， 可促进感染艾滋病毒的细胞或游离病毒从一个人转移到另一个人，以及艾滋病毒感染 艾滋病会增加患某些癌症的风险。HSV-1是一种典型的疱疹病毒 并提供了一个理想的模型来了解病毒感染的要求，因为它 在细胞培养中复制良好，已经开发了许多试剂来研究它。尤其是，对 HSV-1的进入被证明有助于理解EB病毒和卡波西的机制 肉瘤疱疹病毒(KSHV)--人类感染中与癌症相关的两种疱疹病毒。疱疹病毒 进入细胞需要病毒的外膜与细胞膜融合。感染的传播可以 通过传染性病毒或病毒诱导的细胞融合发生。这里描述的研究的最终目标是 了解疱疹病毒，特别是单纯疱疹病毒1型如何诱导膜融合，这是病毒所需的过程 进入和细胞融合。HSV诱导的膜融合的要求包括 四种HSV糖蛋白(Gd，二聚体gHgL复合体和Gb)和特定的细胞受体。我们的 中心假设是，存在于病毒包膜或受感染细胞表面的gD与细胞结合 受体，如Nectin-1，在未感染的细胞上，并通过蛋白质-蛋白质相互作用激活gHgL和GB， 导致了由gB介导的融合。在三个目标中，我们计划定义序列要求和域 Gd、Gh/Gl和Gb是介导膜融合所必需的，并探索稳定Gb SO的方法 那就是可以研究GB的预聚体。这些研究的结果将有助于理解这一机制 疱疹病毒诱导的膜融合及其预防和治疗的新方法 疱疹病毒感染。

Herpesviruses are associated with a variety of disease in the human host, ranging from asymptomatic infections to life threatening disease, including encephalitis and cancer. In addition to playing a direct role in cancer genesis, herpesviruses pose an increased risk to cancer patients who may develop debilitating and life- threatening herpesvirus infections. Genital herpes simplex virus (HSV) lesions, even if clinically not apparent, can facilitate the transfer of HIV-infected cells or free virus from one individual to another, and HIV infection and AIDS increase the risks of developing certain kinds of cancer. HSV-1 serves as a prototypic herpesvirus family member and provides an ideal model to understand the requirements for virus infection since it replicates well in cell culture and many reagents have been developed for its study. In particular, the study of HSV-1 entry has proven useful in the understanding the mechanism of Epstein-Bar Virus (EBV)and Kaposi Sarcoma Herpesvirus (KSHV) – two herpesviruses associated with cancer in human infections. Herpesvirus entry into cells requires fusion of the outer envelope of the virus with a cell membrane. Spread of infection can occur via infectious virus or virus-induced cell fusion. The ultimate objective of studies described here is to understand how herpesviruses, specifically HSV-1, induce membrane fusion, the process required for viral entry and cell fusion. Requirements for HSV-induced membrane fusion include the coordinated activities of four HSV glycoproteins (gD, the hererodimeric gHgL complex, and gB) and specific cellular receptors. Our central hypothesis is that gD, present in the viral envelope or on an infected cell surface, binds to a cellular receptor, such as nectin-1, on an uninfected cell and activates gHgL and gB via protein-protein interactions, resulting in fusion mediated by gB. In three aims, we plan to define the sequence requirements and domains of gD, gH/gL and gB that are required to mediate membrane fusion and to investigate means to stabilize gB so that prefusion gB can be studied. The results of these studies will lead to an understanding of the mechanism of herpesvirus-induced membrane fusion and to new approaches for the prevention and treatment of herpesvirus infections.