Abstract
Human cytomegalovirus (HCMV) encodes four G protein-coupled receptor (GPCR) homologs. Three of these receptors, UL78, US27 and US28, are known for their roles in HCMV dissemination and latency. Despite importance of its rodent orthologs for viral replication and pathogenesis, such a function is not reported for the HCMV-encoded GPCR UL33. Using the clinical HCMV strain Merlin, we show that UL33 facilitates both cell-associated and cell-free virus transmission. A UL33-deficient virus derivative revealed retarded virus spread, formation of less and smaller plaques, and reduced extracellular progeny during multi-cycle growth analysis in fibroblast cultures compared to parental virus. The growth of UL33-revertant, US28-deficient, and US28-revertant viruses were similar to parental virus under multistep growth conditions. UL33- and US28-deficient Merlin viruses impaired cell-associated virus spread to a similar degree. Thus, the growth defect displayed by the UL33-deficient virus but not the US28-deficient virus reflects UL33’s contribution to extracellular transmission. In conclusion, UL33 facilitates cell-associated and cell-free spread of the clinical HCMV strain Merlin in fibroblast cultures.
Highlights
Herpesviruses possess genes acquired from hosts via gene capture events which subsequently have been subjected to evolutionary adaptation to support various aspects of the viral life cycle
While propagating the recombinant viruses derived from these Bacterial Artificial Chromosomes (BAC) in HFFF TR fibroblasts, repressing the transcription of RL13 and the UL128 locus, a growth defect was observed for the UL33-deficient virus
The localization of US28, to a circular perinuclear compartment suggests that deletion of UL33 does not affect the formation of gB, and pp28 to a circular perinuclear compartment suggests that deletion of UL33 does not affect the the Viral Assembly Compartment (VAC)
Summary
Herpesviruses possess genes acquired from hosts via gene capture events which subsequently have been subjected to evolutionary adaptation to support various aspects of the viral life cycle Some of these viral genes encode for G protein-coupled receptors (GPCRs), the largest class of cell surface receptors in eukaryotes and involved in a wide variety of physiological processes [1]. UL78, US27, and US28 have been reported to contribute to the life cycle of HCMV by facilitating cell entry, transport of virion components to the nucleus, extracellular virion release, cell-associated virus spread, migration of infected cells, and establishment of latent infection [10,11,12,13,14,15,16]. US28 facilitates cell-associated dissemination in fibroblasts, but this receptor is dispensable for efficient multistep viral growth
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