Mechanism of Herpes Simplex Virus (HSV) Induced Membrane Fusion

疱疹病毒与人类宿主的多种疾病有关，从无症状的 感染到危及生命的疾病，包括脑炎和癌症。除了直接参与 癌症的发生，疱疹病毒对癌症患者造成的风险增加，这些患者可能会发展为衰弱和生命， 威胁疱疹病毒感染。生殖器单纯疱疹病毒（HSV）病变，即使临床上不明显， 可以促进HIV感染细胞或游离病毒从一个个体转移到另一个个体， 和艾滋病增加了患某些癌症的风险。HSV-1作为一种原型疱疹病毒 家庭成员，并提供了一个理想的模型，以了解病毒感染的要求，因为它 在细胞培养中复制良好，并且已经开发了许多试剂用于其研究。特别是，研究 HSV-1进入已被证明有助于理解Epstein-Bar病毒（EBV）和卡波西（Kaposi）的机制 肉瘤疱疹病毒（KSHV）-两种与人类感染癌症相关的疱疹病毒。疱疹病毒 进入细胞需要病毒的外壳与细胞膜融合。感染的扩散可以 通过感染性病毒或病毒诱导的细胞融合发生。本文所述研究的最终目标是 了解疱疹病毒，特别是HSV-1，如何诱导膜融合，这是病毒感染所需的过程。 进入和细胞融合HSV诱导的膜融合的要求包括以下协调活性： 四种HSV糖蛋白（gD、异二聚体gHgL复合物和gB）和特异性细胞受体。我们 核心假设是存在于病毒包膜或感染细胞表面的gD与细胞膜结合， 受体，如nectin-1，并通过蛋白质-蛋白质相互作用激活gHgL和gB， 导致由gB介导的融合。在三个目标中，我们计划定义序列要求和领域， gD、gH/gL和gB介导膜融合，并研究稳定gB的方法， 可以研究融合前gB。这些研究的结果将导致对机制的理解 疱疹病毒引起的膜融合的新方法以及预防和治疗 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.