An in vitro model for the regulation of human cytomegalovirus latency and reactivation in dendritic cells by chromatin remodelling.
Human cytomegalovirus (HCMV) is a frequent cause of major disease following primary infection or reactivation from latency in immunocompromised patients. Infection of non-permissive mononuclear cells is used for analyses of HCMV latency in vitro. Using this approach, it is shown here that repression of lytic gene expression following experimental infection of CD34+ cells, a site of HCMV latency in vivo, correlates with recruitment of repressive chromatin around the major immediate-early promoter (MIEP). Furthermore, long-term culture of CD34+ cells results in carriage of viral genomes in which the MIEP remains associated with transcriptionally repressive chromatin. Finally, specific differentiation of long-term cultures of infected CD34+ cells to mature dendritic cells results in acetylation of histones bound to the MIEP, concomitant loss of heterochromatin protein 1 and the reactivation of HCMV. These data are consistent with ex vivo analyses of latency and may provide a model for further analyses of the mechanisms involved during latency and reactivation.
Reeves
M B
MB
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Level 5 Box 157, Hills Road, Cambridge CB2 2QQ, UK.
Lehner
P J
PJ
Cambridge Institute for Medical Research, School of Clinical Medicine, University of Cambridge, Addenbrooke's Hospital, Level 5 Box 157, Hills Road, Cambridge CB2 2QQ, UK.
Sissons
J G P
JGP
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Level 5 Box 157, Hills Road, Cambridge CB2 2QQ, UK.
Sinclair
J H
JH
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Level 5 Box 157, Hills Road, Cambridge CB2 2QQ, UK.
D018952:Antigens, CD34 / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D003587:Cytomegalovirus / Q000502:physiology*; D004279:DNA, Viral / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology*; D015967:Gene Expression Regulation, Viral / Q000235:genetics / Q000502:physiology*; D017781:Genes, Immediate-Early; D006801:Humans; D017735:Virus Latency
D018952:Antigens, CD34; D004279:DNA, Viral