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.

人类巨细胞病毒 (HCMV) 是一种 β 疱疹病毒，在世界上大多数人口中终生存在。HCMV 在人群中的持续存在是由于疱疹病毒具有建立潜伏感染的出色能力，该感染逃避宿主免疫反应的消除。病毒如何进出潜伏状态一直是研究重点和争论的热点。流行的范式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) 在潜伏期建立期间表观遗传沉默，并且必须重新激活以使病毒退出潜伏期并重新启动进入生产性复制。虽然很明显 MIEP 因抑制性染色质重塑因子和组蛋白标记的关联而沉默，HCMV 去抑制 MIE 基因表达以重新激活的机制尚不清楚。我们已经确定了 MIE 基因座内的替代启动子元件，这些启动子元件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 CD34+ 人祖细胞再激活的背景下，MIE 转录物主要来源于这些替代启动子的起始。在这里，我们回顾了替代病毒启动子可能调整病毒基因表达控制和特定细胞类型的相应感染模式的机制。