REGULATION OF REPLICATION AND LATENCY BY EBV EBNA-1

儿童时期感染EB病毒（EBV）通常是 无症状。 当主要接触发生在后青春期时， 年EBV引起传染性单核细胞增多症，一种自限性B- 淋巴组织增生性疾病 一旦被感染，一个人会 终身携带病毒，超过80%的成年人 全世界都在潜伏感染 最严重的后遗症 原发性或再活化的EBV感染发生在以下个体中： 免疫功能低下的患者，如 免疫抑制方案与器官 移植，那些与遗传性X连锁免疫缺陷， 艾滋病患者。 EB病毒相关B细胞淋巴瘤可在 这些人群，特别是艾滋病患者， 中枢神经系统淋巴瘤的发病率增加， 舌毛状白斑的发生。 EBV是 与其他两个人群的恶性疾病相关。 的 非洲伯基特淋巴瘤和鼻咽 癌（主要发生在中国提取物中） 含有EBV DNA并表达EBNA-1。 目前可用的抗- 疱疹剂对潜伏复制没有影响。 总 EBV潜伏期维持对EBNA-1的依赖性使EBNA-1成为一种良好的免疫调节剂。 抗病毒靶向的候选者。 详细描述 EBNA-1的结构域和功能，将提供必要的 作为抗病毒策略基础的信息。 这些研究的总体目标是了解 参与维持潜伏的EBV感染。 具体 目的包括：（1）进一步纯化EBNA-1蛋白， 建立了ori-P体外复制系统;（2）分离纯化 和细胞EBNA-1样DNA结合蛋白的表征， (3)EBNA-1的功能结构域的表征;即那些 用于特异性DNA结合，核定位，磷酸化， 染色体联合和反式激活，（4）研究 BamHI-Q结合位点在潜伏基因调控中的作用 （5）ori-P的结构要求分析 功能，和（6）评估潜在的基因表达， 上皮细胞

Infection with Epstein-Barr virus (EBV) during childhood is usually asymptomatic. When primary exposure occurs in the post-adolescent years EBV causes infectious mononucleosis, a self-limiting B- lymphoproliferative disease. Once infected, an individual will carry the virus for life and over 80% of the adult population world-wide is latently infected. The most serious sequelae of primary or reactivated EBV infection occur in individuals who are immunologically compromised such as patients undergoing immunosuppressive regimes in conjunction with organ transplantation, those with genetic X-linked immunodeficiency and AIDS patients. EBV-associated B-cell lymphomas can develop in these populations and in AIDS patients, in particular, there is an increased incidence of lymphoma of the central nervous system and the occurrence of hairy leukoplakia of the tongue. EBV is associated with malignant disease in two other populations. The tumor cells of African Burkitts lymphoma and of nasopharyngeal carcinoma (which occurs primarily in those of Chinese extraction) contain EBV DNA and express EBNA-1. Currently available anti- herpetic agents have no effect on latent replication. The total dependence of EBV latency maintenance on EBNA-1 makes EBNA-1 a good candidate for anti-viral targeting. A detailed characterization of EBNA-1, its domains and functions, would provide necessary information on which to base an anti-viral strategy. The overall goal of these studies is to understand the mechanisms involved in the maintenance of latent EBV infection. The Specific Aims include: (1) Further purification of the EBNA-1 protein and development of an in vitro ori-P replication system, (2) Isolation and characterization of a cellular EBNA-1 like DNA binding protein, (3) Characterization of functional domains of EBNA-1; namely those for specific DNA-binding, nuclear localization, phosphorylation, chromosome association and transactivation, (4) Investigation of a role for the BamHI-Q-binding sites in regulation of latency gene expression, (5) Analysis of structural requirements for ori-P function, and (6) Evaluation of latent gene expression in epithelial cells.