The human cytomegalovirus decathlon: Ten critical replication events provide opportunities for restriction

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous human pathogen that can cause severe disease in immunocompromised individuals, transplant recipients, and to the developing foetus during pregnancy. There is no protective vaccine currently available, and with only a limited number of antiviral drug options, resistant strains are constantly emerging. Successful completion of HCMV replication is an elegant feat from a molecular perspective, with both host and viral processes required at various stages. Remarkably, HCMV and other herpesviruses have protracted replication cycles, large genomes, complex virion structure and complicated nuclear and cytoplasmic replication events. In this review, we outline the 10 essential stages the virus must navigate to successfully complete replication. As each individual event along the replication continuum poses as a potential barrier for restriction, these essential checkpoints represent potential targets for antiviral development.

‘Getting Better’—Is It a Feasible Strategy of Broad Pan-Antiherpesviral Drug Targeting by Using the Nuclear Egress-Directed Mechanism?

“…Through treatments with selective inhibitors of NEC-associated protein kinases, such as viral kinase pUL97-directed MBV, the phosphorylation of nuclear lamins can be blocked. This site-specific phosphorylation, mainly concerning lamin A/C serine 22 [ 51 , 56 ], stands central in the process of the egress-typical reorganization of the nuclear envelope and the formation of lamina-depleted areas [ 51 , 52 , 57 , 105 , 123 , 152 , 153 , 154 , 155 ]. Of note, however, the introduction of a negative charge by phospho-modification is most probably not sufficient to induce such drastic structural changes.…”

Cytomegaloviruses reorganize endomembrane system to intersect endosomal and amphisome-like egress pathway

“…The pathway by which enveloped virions are collected and the biogenesis of multivesicular organelles associated with CMV infection remain poorly understood. It is also not known whether CMVs can also envelop into single vesicles and be released as single virions by direct fusion with the PM, as suggested by ( Turner and Mathias, 2022 ).…”

Human cytomegalovirus mediates APOBEC3B relocalization early during infection through a ribonucleotide reductase-independent mechanism

“…Transcription of IE genes does not require de novo protein synthesis. Immediate-early proteins together with host factors mediate the expression of the kinetically distinct early genes (E), whose products in large part promote viral genome replication and the expression of late genes (L) [reviewed by (16)].…”

“…Congenital HCMV infections are also a leading cause of birth defects [reviewed by (14, 15)]. HCMV has a large double-stranded (ds)DNA genome of 235 kb – the largest among known human herpesviruses – containing 165 canonical open reading frames (ORFs) and several alternative transcripts [reviewed by (16)]. Lytic HCMV infection involves a temporal cascade of gene expression.…”