Abstract
Human cytomegalovirus (HCMV) is a ubiquitous herpesviral pathogen that results in life-long infection. HCMV maintains a latent or quiescent infection in hematopoietic cells, which is broadly defined by transcriptional silencing and the absence of de novo virion production. However, upon cell differentiation coupled with immune dysfunction, the virus can reactivate, which leads to lytic replication in a variety of cell and tissue types. One of the mechanisms controlling the balance between latency and reactivation/lytic replication is the regulation of the major immediate-early (MIE) locus. This enhancer/promoter region is complex, and it is regulated by chromatinization and associated factors, as well as a variety of transcription factors. Herein, we discuss these factors and how they influence the MIE locus, which ultimately impacts the phase of HCMV infection.
Highlights
Human cytomegalovirus (HCMV) is a ubiquitous pathogen that infects 40–60% of the population in developed countries and up to 100% in underdeveloped nations [1]
Latency is characterized by transcriptional silencing, which is due in part to the association of repressive transcription factors that work alongside chromatin remodeling factors discussed above
Canonical NFκB activation requires phosphorylation by a three-subunit IκB kinase (IKK) which subsequently degrades IκB, and in the context of HCMV, this can occur as early as 30 min after lytic infection of fibroblasts [164,194]. It is thought this early induction of NFκB helps initiate major immediate-early (MIE)-driven transcription, in turn accelerating lytic gene expression [162]. While these findings suggest HCMV has evolved to use NFκB to its benefit, the host may leverage this cellular protein’s functions for antiviral countermeasures
Summary
Human cytomegalovirus (HCMV) is a ubiquitous pathogen that infects 40–60% of the population in developed countries and up to 100% in underdeveloped nations [1]. HCMV, like all herpesviruses, transcribes its genes in a highly coordinated temporal cascade categorized into three stages: immediate-early (IE), early (E), and late (L) [34] This is a strictly regulated, stepwise process in which IE gene expression relies solely on host transcription factors and viral tegument proteins and does not depend on de novo protein translation. L genes are expressed, which primarily encode virion structural components, as well as those proteins necessary for packaging and egress [34] During lytic infection, this cascade begins with expression from all five sites of IE gene transcription, regulation of E gene expression is dictated by proteins derived from the major immediate-early (MIE) locus. We discuss the complex regulation of the MIE region and how its control impacts viral infection and HCMV pathogenesis
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