title: In vivo function of the murid herpesvirus-4 ribonucleotide reductase small subunit.
abstract: The difficulty of eliminating herpesvirus carriage makes host entry a key target for infection control. However, its viral requirements are poorly defined. Murid herpesvirus-4 (MuHV-4) can potentially provide insights into gammaherpesvirus host entry. Upper respiratory tract infection requires the MuHV-4 thymidine kinase (TK) and ribonucleotide reductase large subunit (RNR-L), suggesting a need for increased nucleotide production. However, both TK and RNR-L are likely to be multifunctional. We therefore tested further the importance of nucleotide production by disrupting the MuHV-4 ribonucleotide reductase small subunit (RNR-S). This caused a similar attenuation to RNR-L disruption: despite reduced intra-host spread, invasive inoculations still established infection, whereas a non-invasive upper respiratory tract inoculation did so only at high dose. Histological analysis showed that RNR-S(-), RNR-L(-) and TK(-) viruses all infected cells in the olfactory neuroepithelium but unlike wild-type virus then failed to spread. Thus captured host nucleotide metabolism enzymes, up to now defined mainly as important for alphaherpesvirus reactivation in neurons, also have a key role in gammaherpesvirus host entry. This seemed to reflect a requirement for lytic replication to occur in a terminally differentiated cell before a viable pool of latent genomes could be established.
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Milho
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Gill
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Janet S
authors.initials: JS
authors.lastname: May
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Susanna
authors.initials: S
authors.lastname: Colaco
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D006566:Herpesviridae Infections / Q000821:virology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D018144:Rhadinovirus / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D021122:Protein Subunits; D014764:Viral Proteins; D012264:Ribonucleotide Reductases