Regulation of Epstein Barr virus reactivation through the co-activators, CBP/p300

描述(申请人提供)：尽管HAART疗法在美国被广泛用于治疗艾滋病毒感染者，但与EB病毒(EBV)相关的非霍奇金淋巴瘤的发病率并未下降。病毒重新激活是EBV生命周期的一个关键组成部分，与病毒的传播密切相关。揭示控制病毒生命周期这一基本方面的机制对于了解EBV如何促进免疫抑制个体的恶性肿瘤具有重要意义。疱疹病毒的重新激活与细胞周期密切相关。抗-LG、转化生长因子-β、丁酸盐、TPA、IDU等可引起EBV裂解复制的药物可诱导细胞生长停滞。在口腔上皮中，重新激活与最上层的分化有关。此外，在没有外源性诱导剂的情况下，即刻早期裂解反式激活剂Zta可以诱导EBV阳性和EBV阴性细胞的GO/G1生长停滞。因此，人们似乎强烈倾向于在生长受阻的环境中进行EBV裂解复制，这可能会限制病毒DNA复制过程中对核苷酸池的竞争。ZTA介导的反式激活部分是通过与转录共激活因子p300和CBP的结合而发生的；p300和CBP在许多不同的末端分化和生长停滞信号模型中发挥重要作用，p300/CBP功能的中断是病毒癌基因SV40标签和腺病毒E1A转化和促进细胞周期特性所必需的。我们推测，如果生长停滞对于有效的病毒复制很重要，可能会有检查点来确保只有在某些生长停滞信号事件已经完成的情况下才启动裂解复制。我们的初步结果表明，其中一个检查点是Zta介导的转录激活的调节。在这个应用中，我们建议通过抑制p300/CBP介导的反式激活来研究细胞周期促进因子c-Myc和E2F1在调节再激活中的作用。对公众健康的总体意义：EB病毒与许多人类癌症有关，包括鼻咽癌、霍奇金氏病、伯基特淋巴瘤以及艾滋病患者的一些B细胞淋巴瘤。最近，EBV也被认为是特发性肺纤维化的一个重要因素，部分原因是溶解的重新激活。了解潜伏期和再激活之间的转换机制将有助于理解EBV在这些和其他EBV相关疾病中的作用。

DESCRIPTION (provided by applicant): Despite the widespread use of HAART therapy to treat HIV infected individuals in the United States, the incidence of Epstein-Barr virus (EBV) associated non-Hodgkin's lymphomas has not decreased. Viral reactivation is a key component of the EBV life cycle and is intimately associated with spread of the virus. Uncovering the mechanisms governing this fundamental aspect of the viral life cycle is important for developing an understanding of how EBV contributes to malignancies in immunosuppressed individuals. Reactivation in herpesviruses is intimately linked to the cell cycle. Agents that trigger EBV lytic replication, such as anti-lg, TGF-beta, butyrate, TPA, IDU, etc. are known to induce cell growth arrest. In the oral epithelium, reactivation is associated with the upper most differentiated layers. Further, in the absence of exogenous inducing agents, the immediate early lytic transactivator, Zta, can induce a GO/G1 growth arrest in EBV positive and EBV negative cells. Therefore, there appears to be a strong preference for EBV lytic replication to proceed in a growth arrested environment and this may limit competition for nucleotide pools during viral DNA replication. Zta mediated transactivation occurs in part through its association with the transcriptional co-activators, p300 and CBP; p300 and CBP play an important role in a number of different terminal differentiation and growth arrest signaling models and disruption of p300/CBP function is required for the transforming and cell cycle promoting properties of the viral oncogenes, SV40 TAg and adenovirus E1 A. We have postulated that if growth arrest is important for efficient viral replication, there may be checkpoints in place to ensure that lytic replication is initiated only in the case where certain growth arrest signaling events have been accomplished. Our preliminary results indicate that the one such checkpoint is regulation of Zta mediated transcriptional activation. In this application we propose to address the role of the cell cycle promoting factors, c-Myc and E2F1, in modulating reactivation through inhibition of p300/CBP mediated transactivation. Overall significance to public health: EBV is associated with a number of human cancers including nasopharyngeal carcinoma, Hodgkin's disease, Burkitt's lymphoma as well as a number of B-cell lymphomas in AIDS patients. More recently, EBV has also become recognized as a significant contributing factor to idiopathic pulmonary fibrosis which is in part due to lytic reactivation. Understanding the mechanisms governing the transition between latency and reactivation will contribute to the understanding of EBV's role in these and other EBV associated diseases.