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

描述(申请人提供)：EBV是地方性Burkitt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的重要病原体，可导致多种增殖性疾病，包括免疫母细胞淋巴瘤、口腔毛状白斑，以及免疫抑制儿童中一种罕见的肌源性肿瘤。EBV也是其他各种人类恶性肿瘤的一个因素，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。病理学表明EBV在活体内有多种组织趋向性。在体外和体内，最易受EBV感染和允许病毒复制的细胞来自B细胞。主要的病毒包膜糖蛋白350(Gp350)与补体受体2型(CD21)结合，后者在B细胞上大量表达。病毒粒子膜与细胞膜的融合最低限度需要包括Gb、Gh、Gl和GP42在内的病毒蛋白的复合体。已发现GP42与人类白细胞抗原(HLA)II类分子结合，这种相互作用是EB病毒进入B淋巴细胞所必需的。到目前为止，人们对EBV结合和穿透B细胞的机制知之甚少。这项建议将通过结构-功能研究来分析GP42的作用以及它与人类白细胞抗原的相互作用，以促进病毒进入。弄清细胞受体和病毒糖蛋白之间的相互作用对于理解EBV相关疾病背后的取向是至关重要的。公共卫生相关性：这项拟议的研究是朗纳克博士和贾德茨基博士的合作研究计划，旨在确定EB病毒(EBV)进入B淋巴细胞的分子机制，B淋巴细胞是EBV在人类宿主中的主要靶细胞。EBV与多种造血、上皮性和淋巴增生性疾病有关，拟议的研究可能导致确定EBV感染的新疗法以及EBV所属的疱疹病毒家族。

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.