title: Reversible silencing of cytomegalovirus genomes by type I interferon governs virus latency.
abstract: Herpesviruses establish a lifelong latent infection posing the risk for virus reactivation and disease. In cytomegalovirus infection, expression of the major immediate early (IE) genes is a critical checkpoint, driving the lytic replication cycle upon primary infection or reactivation from latency. While it is known that type I interferon (IFN) limits lytic CMV replication, its role in latency and reactivation has not been explored. In the model of mouse CMV infection, we show here that IFNβ blocks mouse CMV replication at the level of IE transcription in IFN-responding endothelial cells and fibroblasts. The IFN-mediated inhibition of IE genes was entirely reversible, arguing that the IFN-effect may be consistent with viral latency. Importantly, the response to IFNβ is stochastic, and MCMV IE transcription and replication were repressed only in IFN-responsive cells, while the IFN-unresponsive cells remained permissive for lytic MCMV infection. IFN blocked the viral lytic replication cycle by upregulating the nuclear domain 10 (ND10) components, PML, Sp100 and Daxx, and their knockdown by shRNA rescued viral replication in the presence of IFNβ. Finally, IFNβ prevented MCMV reactivation from endothelial cells derived from latently infected mice, validating our results in a biologically relevant setting. Therefore, our data do not only define for the first time the molecular mechanism of IFN-mediated control of CMV infection, but also indicate that the reversible inhibition of the virus lytic cycle by IFNβ is consistent with the establishment of CMV latency.
authors.affiliation: Department for Vaccinology/Immune Aging and Chronic Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Dağ
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Lars
authors.initials: L
authors.lastname: Dölken
authors.affiliation: Department for Vaccinology/Immune Aging and Chronic Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Holzki
authors.affiliation: Department for Vaccinology/Immune Aging and Chronic Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Drabig
authors.affiliation: Department for Vaccinology/Immune Aging and Chronic Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Adrien
authors.initials: A
authors.lastname: Weingärtner
authors.affiliation: Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schwerk
authors.affiliation: Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Department for Vaccinology/Immune Aging and Chronic Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Ianina
authors.initials: I
authors.lastname: Conte
authors.affiliation: Department for Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.affiliation: Department of Pediatric Pneumology and Neonatology, Medical School Hannover, Hannover, Germany.
authors.forename: Colin
authors.initials: C
authors.lastname: Davenport
authors.affiliation: Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Ulfert
authors.initials: U
authors.lastname: Rand
authors.affiliation: Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Köster
authors.affiliation: Department of Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiß
authors.affiliation: Department of Virology, Max von Pettenkofer Institute, Ludwig Maximillian University, Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Adler
authors.affiliation: Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wirth
authors.affiliation: Department for Virology, Medical School Hannover, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Messerle
authors.affiliation: Department of Gene Regulation and Differentiation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Hauser
authors.affiliation: Department for Vaccinology/Immune Aging and Chronic Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany ; Department for Virology, Medical School Hannover, Hannover, Germany.
authors.forename: Luka
authors.initials: L
authors.lastname: Cičin-Šain
mesh_terms: D000818:Animals; D002469:Cell Separation; D003587:Cytomegalovirus / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D020868:Gene Silencing; D017781:Genes, Immediate-Early / Q000235:genetics; D016679:Genome, Viral; D059014:High-Throughput Nucleotide Sequencing; D007370:Interferon Type I / Q000235:genetics*; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017735:Virus Latency / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics
chemical_list: D007370:Interferon Type I