REGULATION OF REPLICATION AND LATENCY BY EBV EBNA-1

儿童时期感染EB病毒(EBV)通常是 没有任何症状。当初级接触发生在青春期后 多年的EBV导致传染性单核细胞增多症，一种自我限制性的B- 淋巴增生性疾病。一旦被感染，个人将 终生携带病毒，80%以上的成年人口 全世界都在潜伏着感染。最严重的后遗症是 原发或重新激活的EBV感染发生在符合以下条件的个人中 免疫功能受损，如患者正在接受 免疫抑制疗法与器官联合应用 移植，遗传性X连锁免疫缺陷和 艾滋病患者。EBV相关B细胞淋巴瘤可在 这些人群，特别是艾滋病患者，有一种 中枢神经系统淋巴瘤发病率增加和 舌毛状白斑的发生。EBV是 在另外两个人群中与恶性疾病有关。这个 非洲Burkitts淋巴瘤和鼻咽部肿瘤细胞 癌症(主要发生在中国人的摘除中) 含有EB病毒DNA并表达EBNA-1。目前可用的反- 带状疱疹药物对潜伏复制没有影响。总数 EBV潜伏期维持对EBNA-1的依赖使EBNA-1成为一个很好的选择 抗病毒靶向的候选对象。详细的人物刻画 EBNA-1的结构域和功能，将提供必要的 作为反病毒战略基础的信息。 这些研究的总体目标是了解这些机制 参与维持潜在的EBV感染。具体的 目的包括：(1)进一步纯化EBNA-1蛋白和 OrI-P体外复制系统的建立(2)分离 以及细胞内类似EBNA-1的DNA结合蛋白的鉴定， (3)EBNA-1功能结构域的特征；即 对于特定的DNA结合，核定位，磷酸化， 染色体联合与反式激活，(4)染色体联合与反式激活研究 BamHI-Q结合位点在潜伏期基因调控中的作用 表达，(5)ORI-P的结构要求分析 功能，以及(6)潜在基因表达的评估。 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.