Chromatin structure regulates human cytomegalovirus gene expression during latency, reactivation and lytic infection.
Infection of cells with human cytomegalovirus (HCMV) has two potential outcomes. For instance, infection of fibroblasts results in extensive viral gene expression, viral DNA replication and release of progeny virus. In contrast, in undifferentiated myeloid cells, the lytic transcription programme of HCMV is effectively suppressed and cells undergo latent infection. It is now accepted that the suppression of viral lytic gene expression observed during latency in myeloid cells is a result of the inability of undifferentiated cell types to support robust viral immediate early (IE) gene expression--crucial genes responsible for driving the lytic cycle. The repression of IE gene expression in undifferentiated myeloid cells, at least in part, results from specific post-translational modifications of histones associated with the viral major immediate early promoter (MIEP). In cells of the early myeloid lineage, the histone modifications present on the MIEP impart on it a repressive chromatin structure preventing transcriptional activity. Reactivation of HCMV lytic infection is correlated to changes in histone modifications around the MIEP resulting in a chromatin structure conducive to transcriptional activity. These changes are intimately linked with the differentiation of myeloid cells - a phenomenon known to reactivate latent virus in vivo. Chromatin structure of the viral MIEP, therefore, plays a crucial role in latency and reactivation of this persistent human herpesvirus. Whether chromatin-mediated regulation of viral lytic gene expression also occurs, is only beginning to be addressed. However, recent work suggests that all classes of lytic HCMV promoters are subjected to regulation by post-translational modification of their associated histones throughout the time course of infection. Incoming viral genomes appear to be the targets of intrinsic cellular defence mechanisms which attempt to silence viral gene expression through chromatinisation. Viral functions eventually overcome these cellular repression mechanisms permitting high levels of IE gene expression which results in modification of the chromatin structure of early and late gene promoters driving a regulated cascade of viral lytic gene expression and virus production.
Sinclair
John
J
Department of Medicine, Level 5, Addenbrooke's Hospital, University of Cambridge, Hills Rd, Cambridge CB22QQ, UK. js@mole.bio.cam.ac.uk
D002843:Chromatin / Q000737:chemistry*; D003587:Cytomegalovirus / Q000235:genetics*; D015967:Gene Expression Regulation, Viral; D006801:Humans; D011499:Protein Processing, Post-Translational; D014775:Virus Activation; D017735:Virus Latency; D014779:Virus Replication
D002843:Chromatin