Chromatin control of human cytomegalovirus infection

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.

cGAS-STING-TBK1 Signaling Promotes Valproic Acid-Responsive Human Cytomegalovirus Immediate-Early Transcription during Infection of Incompletely Differentiated Myeloid Cells

“…During de novo lytic infection in differentiated cells, the MIEP is rapidly activated by tegument-delivered viral transactivators and is associated with a transcriptionally activating chromatin structure [ 17 , 18 ]. In contrast, during the establishment of latency, the MIEP is assembled into heterochromatin and transcription from this locus is suppressed [ 11 , 17 , 19 ]. Both cellular and viral proteins contribute to the repression of the MIEP during latency [ 11 , 20 ].…”

Host-encoded CTCF regulates human cytomegalovirus latency via chromatin looping

“…HCMV latency is maintained within cells of the myeloid lineage through the epigenetic control of viral transcription. During viral latent infection, a limited number of viral transcripts are synthesized, although major immediate early (MIE) gene expression is repressed (5). Transcription from the MIE locus is driven by the MIE promoter (MIEP), as well as additional alternative promoters that function in specific contexts (6), and activation of these promoters is regulated through chromatinization, as well as various transcription factors (7, 8).…”

“…Transcription from the MIE locus is driven by the MIE promoter (MIEP), as well as additional alternative promoters that function in specific contexts (6), and activation of these promoters is regulated through chromatinization, as well as various transcription factors (7, 8). During reactivation, however, the MIEP becomes derepressed as the virus switches to a lytic infection and is able to fully replicate (5).…”

c-Jun Signaling During Initial HSV-1 Infection Modulates Latency to Enhance Later Reactivation in addition to Directly Promoting the Progression to Full Reactivation

“…The Herpesviruses establish lifelong latent infections within specific host cells and periodically reactivate to permit transmission. During latent infection, the double-stranded DNA herpesvirus genomes reside in an epigenetically silent state, coated with host histone proteins within host nuclei (1)(2)(3)(4)(5)(6). The transcription of viral lytic mRNAs is largely repressed and therefore viral proteins that mediate lytic gene transactivation during productive infection are largely absent.…”