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

描述（由申请人提供）：尽管在美国广泛使用HAART疗法治疗HIV感染个体，但EB病毒（EBV）相关非霍奇金淋巴瘤的发病率并未降低。病毒再活化是EBV生命周期的关键组成部分，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如何导致免疫抑制个体的恶性肿瘤非常重要。疱疹病毒的再活化与细胞周期密切相关。已知触发EBV裂解性复制的试剂，如抗Ig、TGF-β、丁酸盐、TPA、IDU等诱导细胞生长停滞。在口腔上皮中，再活化与最上层的分化层有关。此外，在不存在外源诱导剂的情况下，立即早期裂解反式激活因子Zta可以在EBV阳性和EBV阴性细胞中诱导GO/G1生长停滞。因此，似乎有一个强烈的偏好，EBV裂解复制进行生长停滞的环境中，这可能会限制竞争的核苷酸库在病毒DNA复制。Zta介导的反式激活部分地通过其与转录共激活因子p300和CBP的结合而发生; p300和CBP在许多不同的终末分化和生长停滞信号传导模型中起重要作用，并且p300/CBP功能的破坏是病毒癌基因SV 40 TAg和腺病毒ElA的转化和细胞周期促进特性所需的。我们已经假设，如果生长停滞对于有效的病毒复制是重要的，则可能存在适当的检查点以确保仅在某些生长停滞信号传导事件已经完成的情况下才启动裂解性复制。我们的初步结果表明，这样的一个检查点是调节Zta介导的转录激活。在本申请中，我们提出了解决的作用，细胞周期促进因子，c-Myc和E2 F1，通过抑制p300/CBP介导的反式激活调节再激活。对公共卫生的总体意义：EB病毒与许多人类癌症有关，包括鼻咽癌、霍奇金病、伯基特淋巴瘤以及艾滋病患者的许多B细胞淋巴瘤。最近，EBV也被认为是特发性肺纤维化的重要促成因素，其部分原因是溶解性再活化。了解潜伏期和再激活之间的过渡机制将有助于理解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.