Mechanism of Herpes Simplex Virus (HSV) Induced Membrane Fusion

单纯疱疹病毒（HSV）诱导膜融合的机制

• 批准号: 10530595
• 负责人: Sarah A. Connolly
• 金额: $ 54.69万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530595
• 关键词: Binding; Biochemical; Biological Assay; Blindness; C-terminal; Cancer Patient; Cell Culture Techniques; Cell fusion; Cell membrane; Cell surface; Cells; Chimera organism; Chimeric Proteins; Clinical; Coiled-Coil Domain; Complex; Cryoelectron Microscopy; Cytoplasmic Tail; Data; Disease; Encephalitis; Evolution; Experimental Designs; Family; Family member; Glycoproteins; HIV; HIV Infections; HIV/AIDS; Herpesviridae; Herpesviridae Infections; Herpesvirus 1; Human; Human Herpesvirus 4; Human Herpesvirus 8; In Vitro; Individual; Infection; Left; Lesion; Life; Malignant Neoplasms; Maps; Mediating; Membrane; Membrane Fusion; Methodology; Modeling; Molecular; Molecular Conformation; Morbidity - disease rate; Mutagenesis; Mutation; Natural Selections; Nature; PVRL1; Pathology; Penetration; Play; Population; Prevention approach; Process; Proteins; Publishing; Reagent; Research; Risk; Role; Saimiriine herpesvirus 1; Serial Passage; Simplexvirus; Site; Site-Directed Mutagenesis; Structure; Therapeutic; Transmembrane Domain; Viral; Virus; Virus Diseases; Virus-Induced Membrane Fusion; Work; arm; design; experimental study; genetic approach; genital herpes; insight; mutant; novel; novel strategies; prophylactic; protein protein interaction; prototype; receptor; tool; virus envelope

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.

疱疹病毒与人类宿主的多种疾病有关，包括无症状的 感染危及生命的疾病，包括脑炎和癌症。除了直接发挥作用外 癌症发生过程中，疱疹病毒给癌症患者带来了更大的风险，这些患者可能会变得衰弱和生命垂危。 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 家庭成员，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，并且已经开发了许多试剂用于其研究。特别是，研究 HSV-1 条目已被证明有助于理解 Epstein-Bar 病毒 (EBV) 和卡波西病毒的机制 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 HSV-1，如何诱导膜融合，这是病毒形成所需的过程 进入和细胞融合。 HSV 诱导的膜融合的要求包括协调活动 四种 HSV 糖蛋白（gD、异二聚体 gHgL 复合物和 gB）和特定细胞受体。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 未感染细胞上的受体，例如 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 是介导膜融合和研究稳定 gB 的方法所必需的 可以研究预融合 gB。这些研究的结果将有助于理解其机制 疱疹病毒诱导的膜融合的研究以及预防和治疗疱疹病毒的新方法 疱疹病毒感染。