Mechanisms of Reactivation of Epstein-Barr Virus from Latency to Lytic Replicatio

EB病毒(Epstein-Barr Virus，EBV)是一种普遍存在的人类疱疹病毒，可感染B淋巴细胞和上皮细胞。根据细胞类型及其分化状态的不同，EBV感染可导致细胞死亡的裂解复制或潜伏感染。潜伏的EBV感染与多种B细胞和上皮细胞恶性肿瘤有关，包括Burkitt淋巴瘤、霍奇金氏病、免疫受损个体的非霍奇金淋巴瘤、鼻咽癌和一些胃癌。因此，了解EBV潜伏期与溶血性复制的调节对于开发治疗这些疾病的方法至关重要。EBV的BZLF1和BRLF1基因编码裂解复制所必需的多功能蛋白。虽然BZLF1和BRLF1启动子在潜伏感染的细胞中没有活性，但细胞分化和某些细胞信号通路的激活剂可以诱导BZLF1和BRLF1的表达，促进EBV重新激活进入裂解复制。在这个项目中，我们将(I)确定在调节这两个即刻早期基因在B细胞和上皮细胞中的表达方面起关键作用的细胞因素，以及(Ii) 研究这些因素如何有助于在各种细胞类型和细胞分化过程中控制潜伏和裂解的EBV感染之间的平衡。结合项目5，这些结果可能会导致治疗EBV相关癌症的新疗法。

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus virus that can infect both B lymphocytes and epithelial cells. Depending upon the cell type and its state of differentiation, infection by EBV leads to either lytic replication with cell death or a latent infection. Latent EBV infections are associated with several B-cell and epithelial-cell malignancies including Burkitt's lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas in immunocompromised individuals, nasopharyngeal carcinoma, and some gastric carcinomas. Thus, understanding regulation of EBV latency versus lytic replication is crucial for developing therapies to treat these diseases. The BZLF1 and BRLF1 genes of EBV encode multifunctional proteins essential for lytic replication. While the BZLF1 and BRLF1 promoters are inactive in latently infected cells, cell differentiation and activators of certain cell signaling pathways can induce BZLF1 and BRLF1 expression, promoting EBV reactivation into lytic replication. In this Project, we will (i) identify cellular factors that play key roles in regulating expression of these two immediate-early genes in both B cells and epithelial cells, and (ii) examine how these factors contribute to controlling the balance between latent and lytic EBV infection in a variety of cell types and during cellular differentiation. In conjunction with Project 5, these results may lead to new therapies for treating EBV-associated cancers.