title: Human cytomegalovirus miR-UL112-1 promotes the down-regulation of viral immediate early-gene expression during latency to prevent T-cell recognition of latently infected cells.
abstract: Human cytomegalovirus, a member of the herpesvirus family, can cause significant morbidity and mortality in immune compromised patients resulting from either primary lytic infection or reactivation from latency. Latent infection is associated with a restricted viral transcription programme compared to lytic infection which consists of defined protein coding RNAs but also includes a number of virally encoded microRNAs (miRNAs). One of these, miR-UL112-1, is known to target the major lytic IE72 transcript but, to date, a functional role for miR-UL112-1 during latent infection has not been shown. To address this, we have analysed latent infection in myeloid cells using a virus in which the target site for miR-UL112-1 in the 3' UTR of IE72 was removed such that any IE72 RNA present during latent infection would no longer be subject to regulation by miR-UL112-1 through the RNAi pathway. Our data show that removal of the miR-UL112-1 target site in IE72 results in increased levels of IE72 RNA in experimentally latent primary monocytes. Furthermore, this resulted in induction of immediate early (IE) gene expression that is detectable by IE-specific cytotoxic T-cells (CTLs); no such CTL recognition of monocytes latently infected with wild-type virus was observed. We also recapitulated these findings in the more tractable THP-1 cell line model of latency. These observations argue that an important role for miR-UL112-1 during latency is to ensure tight control of lytic viral immediate early (IE) gene expression thereby preventing recognition of latently infected cells by the host's potent pre-existing anti-viral CTL response.
authors.affiliation: Department of Medicine, University of Cambridge, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Betty
authors.initials: B
authors.lastname: Lau
authors.affiliation: Department of Medicine, University of Cambridge, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Poole
authors.affiliation: Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Van Damme
authors.affiliation: Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Lieve
authors.initials: L
authors.lastname: Bunkens
authors.affiliation: Department of Medicine, University of Cambridge, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Sowash
authors.affiliation: Department of Medicine, University of Cambridge, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Harry
authors.initials: H
authors.lastname: King
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Eain
authors.initials: E
authors.lastname: Murphy
authors.affiliation: Department of Medicine, University of Cambridge, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Wills
authors.affiliation: Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Marnix
authors.initials: M
authors.lastname: Van Loock
authors.affiliation: Department of Medicine, University of Cambridge, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Sinclair
mesh_terms: D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D015536:Down-Regulation; D015870:Gene Expression; D015967:Gene Expression Regulation, Viral; D017781:Genes, Immediate-Early; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D057131:Immune Evasion; D035683:MicroRNAs / Q000378:metabolism*; D009000:Monocytes / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D017735:Virus Latency
chemical_list: C088645:IE1 protein, cytomegalovirus; D017874:Immediate-Early Proteins; D035683:MicroRNAs; C000599836:microRNA-UL112, human cytomegalovirus