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Review
. 2023 Aug 31;14(4):e0032623.
doi: 10.1128/mbio.00326-23. Epub 2023 Jul 13.

Chromatin control of human cytomegalovirus infection

Stephen M Matthews  1 , Ian J Groves  1   2 , Christine M O'Connor  1   2
Affiliations
Review

Chromatin control of human cytomegalovirus infection

Stephen M Matthews et al. mBio. .

Abstract

Human cytomegalovirus (HCMV) is a betaherpesvirus that establishes lifelong infection in its host and can cause severe comorbidities in individuals with suppressed or compromised immune systems. The lifecycle of HCMV consists of lytic and latent phases, largely dependent upon the cell type infected and whether transcription from the major immediate early locus can ensue. Control of this locus, which acts as a critical "switch" region from where the lytic gene expression cascade originates, as well as regulation of the additional ~235 kilobases of virus genome, occurs through chromatinization with cellular histone proteins after infection. Upon infection of a host cell, an initial intrinsic antiviral response represses gene expression from the incoming genome, which is relieved in permissive cells by viral and host factors in concert. Latency is established in a subset of hematopoietic cells, during which viral transcription is largely repressed while the genome is maintained. As these latently infected cells differentiate, the cellular milieu and epigenetic modifications change, giving rise to the initial stages of virus reactivation from latency. Thus, throughout the cycle of infection, chromatinization, chromatin modifiers, and the recruitment of specific transcription factors influence the expression of genes from the HCMV genome. In this review, we discuss epigenetic regulation of the HCMV genome during the different phases of infection, with an emphasis on recent reports that add to our current perspective.

Keywords: CMV; HHV; chromatin; cytomegalovirus; epigenetics; herpesvirus; histone; transcription factors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig 1
Fig 1
The HCMV lifecycle. Initial infection with HCMV begins with exposure of mucosal epithelia to infectious body fluid (e.g., saliva and urine). Infection of permissive cells, including endothelial and epithelial cells, results in lytic infection and the production of infectious virus capable of spread within and among human hosts. By mechanisms that remain poorly understood, hematopoietic cells of the myeloid lineage, namely CD14+ monocytes and CD34+ HPCs become infected and support latency, defined by maintenance of the viral genome in the absence of robust viral gene expression and virion production. As infected cells differentiate into macrophage or dendritic cells, or are exposed to specific stressors (e.g., hypoxia or inflammation), the virus reactivates, ultimately leading to lytic replication and the production of infectious virus. The newly produced virions can disseminate, reseed the latent reservoir, and spread to new hosts. During both initial infection and reactivation, a competent immune system can detect and curb the spread of HCMV, resulting in few to no clinical symptoms.
Fig 2
Fig 2
Epigenetic modulation regulates HCMV gene expression during infection. After nuclear entry, the double-stranded DNA HCMV genome is circularized and rapidly associated with histones, forming nucleosomes. Through chromatinization, host nuclear factors, like Daxx at PML-NBs, repress transcription at this pre-immediate early (Pre-IE) stage. Tegument-associated proteins, like pp71, are delivered to cells with the incoming virus and regulate host factors in permissive cells to promote IE gene expression via transcriptional activation of the major immediate early promoter (MIEP). However, upon infection of myeloid cells, the majority of the HCMV genome is heterochromatinized via repressive enzymes (e.g., HDACs and PRC2) and transcription factors (e.g., KAP1) such that latent infection ensues. A subset of viral proteins, including LUNA, is expressed to help maintain latency and enable efficient reactivation. De-repression of the MIEP by host factors (e.g., KDM6B demethylases) and production of IE72/IE86 proteins initiate early gene expression. IE86, along with host factors, then auto-represses the MIEP, before DNA replication and Late gene expression occur. Following DNA replication, either chromatinization of daughter genomes is lost or a subpopulation remains unbound by histones, and thus, naked dsDNA genomes are packaged into de novo formed capsids prior to virus egress. Nucleosomes specifically associated with the MIEP are noted by yellow DNA wrapping the nucleosome (see inset).
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