Structural and Functional Studies of gp42 and HLA Class II in EBV Entry

描述（由申请人提供）：EBV是地方性伯基特淋巴瘤和未分化鼻咽癌（NPC）的病原体。EBV也被认为是免疫抑制个体中的重要病原体，引起多种增殖性疾病，包括免疫母细胞淋巴瘤、口腔毛状白斑和免疫抑制儿童中的罕见肌肉来源肿瘤。EBV也是多种其他人类恶性肿瘤的因子，包括一些T细胞淋巴瘤、霍奇金淋巴瘤、伯基特淋巴瘤和胃癌。病理学提示EBV在体内具有多种组织嗜性。在体外和体内，最易受EBV感染并允许病毒复制的细胞是B细胞来源的。主要的病毒包膜糖蛋白350（gp 350）与在B细胞上大量表达的补体受体2型（CD 21）结合。病毒体膜与细胞膜的融合最低限度地需要包括gB、gH、gL和gp 42的病毒蛋白复合物。已经发现gp 42特异性地结合人白细胞抗原（HLA）II类，并且这种相互作用是EBV进入B淋巴细胞所必需的。迄今为止，人们对EBV结合和穿透B细胞的机制知之甚少。本研究拟通过结构-功能研究来分析gp 42在病毒进入细胞中的作用及其与HLA的相互作用。阐明细胞受体和病毒糖蛋白之间的相互作用对于理解EBV相关疾病背后的向性至关重要。 公共卫生相关性：这项拟议的研究代表了Longnecker博士和Jardetzky博士之间的合作研究计划，以确定EB病毒（EBV）进入B淋巴细胞（EBV在人类宿主中的主要靶细胞）的分子机制。EBV与多种造血、上皮和淋巴组织增生性疾病相关，拟议的研究可能导致鉴定EBV感染的新疗法以及EBV作为成员的疱疹病毒家族。

DESCRIPTION (provided by applicant): EBV is a causative agent in endemic Burkitt's lymphoma and undifferentiated nasopharyngeal carcinoma (NPC). EBV is also recognized as an important pathogen in immunosuppressed individuals, causing a variety of proliferative disorders including immunoblastic lymphomas, oral hairy leukoplakia, and an unusual tumor of muscle origin in immunosuppressed children. EBV is also a factor in a variety of other human malignancies including some T-cell lymphomas, Hodgkin lymphoma, Burkitt's lymphoma, and gastric carcinoma. The pathologies suggest a wide variety of tissue tropism for EBV in vivo. In vitro and in vivo, the cells that are most susceptible to EBV infection and permissive for viral replication are of B cell origin. The major viral envelope glycoprotein 350 (gp350) binds to the complement receptor type two (CD21) that is abundantly expressed on B cells. Fusion of the virion membrane with the cell membrane minimally requires a complex of viral proteins that includes gB, gH, gL, and gp42. gp42 has been specifically found to bind to human leukocyte antigen (HLA) class II and this interaction is required for EBV entry into B lymphocytes. To date, little is known about the mechanism that EBV uses to bind and penetrate B cells. This proposal will analyze the role of gp42 and its interaction with HLA for viral entry by structure-function studies. Clarifying the interactions between cellular receptors and viral glycoproteins is essential for understanding the tropisms behind EBV associated diseases. PUBLIC HEALTH RELEVANCE: This proposed research represents a collaborative research program between Dr. Longnecker and Dr. Jardetzky to define the molecular mechanisms involved in Epstein-Barr virus (EBV) entry into B lymphocytes, the major target cell of EBV in human hosts. EBV is associated with a variety of hematopoietic, epithelial, and lymphoproliferative diseases and the proposed research may result in the identification of new therapeutics for EBV infections as well as the herpesvirus family in general of which EBV is a member.