Transcriptional Control of Human Cytomegalovirus Latency

摘要 潜伏期允许人类巨细胞病毒(HCMV)通过避免 免疫检测和清除。该病毒潜伏持续并高效地重新激活的能力是 人巨细胞病毒感染引发严重医疗问题的主要因素。未分化的人巨细胞病毒潜伏 髓系细胞，并在这些细胞分化时重新激活。立即早期1(IE1)蛋白是一种 促进病毒裂解阶段进展的转录因子。潜伏期内溶血素水平 (生产)相蛋白质，如IE1，保持极低水平(或完全不存在)，因为 主要的即刻早期启动子(MIEP)在转录水平上被沉默 通过异染色质。假信号提前触发未分化髓系细胞的裂解周期 像IE1这样的蛋白质的产生可能会在HCMV之前导致对重新激活的细胞的免疫破坏 完成富有成效的一轮复制。保持全长IE1蛋白水平较低或缺乏保护作用 潜伏感染细胞的免疫监视，并限制重新激活事件，直到细胞分化。 我们的实验室证明了细胞蛋白Daxx和相关的组蛋白脱乙酰酶(HDAC)可以沉默 当HCMV建立潜伏期时，MEP。同样，我们还发表了病毒UL138蛋白沉默 IE1在潜伏期通过抑制赖氨酸特异性去甲基酶的募集而转录 (KDMS)到MIEP，去除抑制的表观遗传组蛋白甲基化以激活转录。在……里面 目标1，我们建议定义UL138如何防止KDM重新招募到MIEP并使IE1沉默 在高尔基体定位的潜伏期转录。从巨细胞病毒中删除UL138 基因组显示，至少还有一个IE1转录抑制因子是由临床菌株编码的。是这样的 使MIEP沉默的功能冗余强调了这一进程对全世界的重要性 人巨细胞瘤病毒治疗成功。我们现在已经鉴定了这个新的IE转录抑制子。在目标2中，我们建议 以确定它在潜伏期如何抑制MIEP。知道MIEP如何在延迟期间静音 应该揭示IE1转录可以被控制为抑制或诱导的机制 从潜伏期重新激活以获得治疗效果。

Abstract Latency permits human cytomegalovirus (HCMV) to colonize its hosts for their lifetime by avoiding immune detection and clearance. The abilities of the virus to persist latently and reactivate productively are major factors in the serious medical issues caused by HCMV infections. HCMV is latent in undifferentiated myeloid cells and reactivates when these cells differentiate. The Immediate Early 1 (IE1) protein is a transcription factor that promotes progression through the viral lytic phase. During latency the levels of lytic (productive) phase proteins such as IE1 are kept extremely low (or completely absent) because the promoter that drives its expression, the Major Immediate Early Promoter (MIEP) is transcriptionally silenced by heterochromatin. Premature triggering of the lytic cycle in undifferentiated myeloid cells by spurious production of proteins like IE1 likely results in immune destruction of the reactivating cell before HCMV can complete a productive round of replication. Keeping full length IE1 protein levels low or absent protects latently infected cells from immune surveillance and restricts reactivation events until the cell differentiates. Our lab demonstrated the cellular protein Daxx and an associated histone deacetylase (HDAC) silences the MIEP when HCMV establishes latency. Likewise, we also published that the viral UL138 protein silences IE1 transcription during latency by inhibiting the recruitment of lysine-specific demethylases (KDMs) to the MIEP that remove repressive epigenetic histone methylations to activate transcription. In Aim 1, we propose to define how UL138 prevents KDM recruitment to the MIEP and silences IE1 transcription during latency from its localization at the Golgi apparatus. Deletion of UL138 from the HCMV genome revealed that at least one more suppressor of IE1 transcription is encoded by clinical strains. Such functional redundancy in silencing the MIEP underscores the importance of this process for the worldwide success of HCMV. We have now identified this novel silencer of IE transcription. In Aim 2 we propose to determine how it represses the MIEP during latency. Knowing how the MIEP is silenced during latency should reveal mechanisms through which IE1 transcription can be controlled to either inhibit or induce reactivation from latency for therapeutic effect.