Abstract
Lytic infection of differentiated cell types with human cytomegalovirus (HCMV) results in the temporal expression of between 170–200 open reading frames (ORFs). A number of studies have demonstrated the temporal regulation of these ORFs and that this is orchestrated by both viral and cellular mechanisms associated with the co-ordinated recruitment of transcription complexes and, more recently, higher order chromatin structure. Importantly, HCMV, like all herpes viruses, establishes a lifelong latent infection of the host—one major site of latency being the undifferentiated haematopoietic progenitor cells resident in the bone marrow. Crucially, the establishment of latency is concomitant with the recruitment of cellular enzymes that promote extensive methylation of histones bound to the major immediate early promoter. As such, the repressive chromatin structure formed at the major immediate early promoter (MIEP) elicits inhibition of IE gene expression and is a major factor involved in maintenance of HCMV latency. However, it is becoming increasingly clear that a distinct subset of viral genes is also expressed during latency. In this review, we will discuss the mechanisms that control the expression of these latency-associated transcripts and illustrate that regulation of these latency-associated promoters is also subject to chromatin mediated regulation and that the instructive observations previously reported regarding the negative regulation of the MIEP during latency are paralleled in the regulation of latent gene expression.
Highlights
Human cytomegalovirus (HCMV) is an opportunistic pathogen that, like all herpes viruses, can establish a latent infection that persists for the lifetime of the host
Suggestive that expression is dependent on IE gene expression during lytic infection, the first insights into the regulation of the UL144 promoter came from an analysis of different HCMV isolates during latent infection of myeloid progenitor cells and, interestingly, suggested some parallels to those observed with Latency Unique Nuclear Antigen (LUNA) [47]
It is becoming increasingly clear that the regulation of cytomegalovirus gene expression during all phases of lytic infection involves post-translational modification of histone proteins
Summary
Human cytomegalovirus (HCMV) is an opportunistic pathogen that, like all herpes viruses, can establish a latent infection that persists for the lifetime of the host. With the advent of more sensitive high throughput screening techniques, the identification of a small number of latency associated transcripts (which, in most cases, are expressed during lytic infection) has been possible These transcripts expressed during latent infection are from viral genes dispersed throughout the viral genome, suggesting that no one region is ‘latently active’ but rather that latency-associated transcripts are regulated independently by specific promoters. In this short review, we will present the current status of our knowledge regarding the regulation of expression of the latency associated transcripts of HCMV and its relationship to post-translational modifications of histones
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