Control of Immediate Early Gene Expression for Human Cytomegalovirus Reactivation.
Control of Immediate Early Gene Expression for Human Cytomegalovirus Reactivation.
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DOI：
10.3389/fcimb.2020.00476
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发表时间：
2020
影响因子：
5.7
通讯作者：
Goodrum F
中科院分区：
文献类型：
--
作者：
Collins-McMillen D;Kamil J;Moorman N;Goodrum F
人巨细胞病毒（HCMV）是一种β疱疹病毒，在世界大多数人口中持续存在。HCMV在人群中的持续存在是由于疱疹病毒建立潜伏感染的精致能力，该潜伏感染逃避宿主免疫应答的消除。病毒如何进入和离开潜伏状态一直是研究焦点和争论的激烈领域。流行的范例是驱动主要立即早期（MIE）反式激活因子的稳健表达的主要立即早期启动子（MIEP）在潜伏期建立期间被表观遗传学沉默，并且必须被重新激活以使病毒退出潜伏期并重新进入生产性复制。虽然MIEP被抑制性染色质重塑因子和组蛋白标记物的结合所沉默是清楚的，但HCMV去抑制MIE基因表达以重新激活的机制还不太清楚。我们已经确定了MIE基因座内的替代启动子元件，其在生产性感染期间驱动MIE基因表达的第二阶段或延迟阶段。在THP-1巨噬细胞和原代CD 34+人祖细胞中再活化的情况下，MIE转录物主要来源于这些替代启动子的起始。在这里，我们审查的机制，替代病毒启动子可能会定制控制病毒基因表达和相应的模式感染特定的细胞类型。HCMV MIE基因座的替代启动子控制增加了系统的多功能性，并允许病毒紧密抑制病毒基因表达的潜伏期，但保留了感知和响应细胞类型特异性宿主信号的能力，以重新激活复制。
Human cytomegalovirus (HCMV) is a beta herpesvirus that persists for life in the majority of the world's population. The persistence of HCMV in the human population is due to the exquisite ability of herpesviruses to establish a latent infection that evades elimination by the host immune response. How the virus moves into and out of the latent state has been an intense area of research focus and debate. The prevailing paradigm is that the major immediate early promoter (MIEP), which drives robust expression of the major immediate early (MIE) transactivators, is epigenetically silenced during the establishment of latency, and must be reactivated for the virus to exit latency and re-enter productive replication. While it is clear that the MIEP is silenced by the association of repressive chromatin remodeling factors and histone marks, the mechanisms by which HCMV de-represses MIE gene expression for reactivation are less well understood. We have identified alternative promoter elements within the MIE locus that drive a second or delayed phase of MIE gene expression during productive infection. In the context of reactivation in THP-1 macrophages and primary CD34+ human progenitor cells, MIE transcripts are predominantly derived from initiation at these alternative promoters. Here we review the mechanisms by which alternative viral promoters might tailor the control of viral gene expression and the corresponding pattern of infection to specific cell types. Alternative promoter control of the HCMV MIE locus increases versatility in the system and allows the virus to tightly repress viral gene expression for latency but retain the ability to sense and respond to cell type-specific host cues for reactivation of replication.