title: An investigation of herpes simplex virus promoter activity compatible with latency establishment reveals VP16-independent activation of immediate-early promoters in sensory neurones.
abstract: Herpes simplex virus (HSV) type-1 establishes lifelong latency in sensory neurones and it is widely assumed that latency is the consequence of a failure to initiate virus immediate-early (IE) gene expression. However, using a Cre reporter mouse system in conjunction with Cre-expressing HSV-1 recombinants we have previously shown that activation of the IE ICP0 promoter can precede latency establishment in at least 30% of latently infected cells. During productive infection of non-neuronal cells, IE promoter activation is largely dependent on the transactivator VP16 a late structural component of the virion. Of significance, VP16 has recently been shown to exhibit altered regulation in neurones; where its de novo synthesis is necessary for IE gene expression during both lytic infection and reactivation from latency. In the current study, we utilized the Cre reporter mouse model system to characterize the full extent of viral promoter activity compatible with cell survival and latency establishment. In contrast to the high frequency activation of representative IE promoters prior to latency establishment, cell marking using a virus recombinant expressing Cre under VP16 promoter control was very inefficient. Furthermore, infection of neuronal cultures with VP16 mutants reveals a strong VP16 requirement for IE promoter activity in non-neuronal cells, but not sensory neurones. We conclude that only IE promoter activation can efficiently precede latency establishment and that this activation is likely to occur through a VP16-independent mechanism.
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: João T
authors.initials: JT
authors.lastname: Proença
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Coleman
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Nicoll
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Viv
authors.initials: V
authors.lastname: Connor
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, 8 Church Street, Glasgow G11 5JR, Scotland, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Preston
authors.affiliation: Microbiology and Infectious Diseases Laboratories, Institute of Medical and Veterinary Science, Frome Road, Adelaide 5000, Australia.|Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Arthur
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
authors.forename: Stacey
authors.initials: S
authors.lastname: Efstathiou
mesh_terms: D000818:Animals; D005260:Female; D015967:Gene Expression Regulation, Viral; D017781:Genes, Immediate-Early; D017405:Herpes Simplex Virus Protein Vmw65 / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011984:Sensory Receptor Cells / Q000821:virology*; D017735:Virus Latency
chemical_list: D017405:Herpes Simplex Virus Protein Vmw65