title: Latency-associated viral interleukin-10 (IL-10) encoded by human cytomegalovirus modulates cellular IL-10 and CCL8 Secretion during latent infection through changes in the cellular microRNA hsa-miR-92a.
abstract: The UL111A gene of human cytomegalovirus encodes a viral homologue of the cellular immunomodulatory cytokine interleukin 10 (cIL-10), which, due to alternative splicing, results in expression of two isoforms designated LAcmvIL-10 (expressed during both lytic and latent infection) and cmvIL-10 (identified only during lytic infection). We have analyzed the functions of LAcmvIL-10 during latent infection of primary myeloid progenitor cells and found that LAcmvIL-10 is responsible, at least in part, for the known increase in secretion of cellular IL-10 and CCL8 in the secretomes of latently infected cells. This latency-associated increase in CCL8 expression results from a concomitant LAcmvIL-10-mediated suppression of the expression of the cellular microRNA (miRNA) hsa-miR-92a, which targets CCL8 directly. Taking the data together, we show that the previously observed downregulation of hsa-miR-92a and upregulation of CCL8 during HCMV latent infection of myeloid cells are intimately linked via the latency-associated expression of LAcmvIL-10.
  
  
  OBJECTIVE
  HCMV latency causes significant morbidity and mortality in immunocompromised individuals, yet HCMV is carried silently (latently) in 50 to 90% of the population. Understanding how HCMV maintains infection for the lifetime of an infected individual is critical for the treatment of immunocompromised individuals suffering with disease as a result of HCMV. In this study, we analyze one of the proteins that are expressed during the "latent" phase of HCMV, LAcmvIL-10, and find that the expression of the gene modulates the microenvironment of the infected cell, leading to evasion of the immune system.
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Poole
authors.affiliation: Human Cytomegalovirus Research Group, Discipline of Infectious Diseases and Immunology, University of Sydney Camperdown, Camperdown, NSW, Australia.
authors.forename: Selmir
authors.initials: S
authors.lastname: Avdic
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Jemima
authors.initials: J
authors.lastname: Hodkinson
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jackson
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Wills
authors.affiliation: Human Cytomegalovirus Research Group, Discipline of Infectious Diseases and Immunology, University of Sydney Camperdown, Camperdown, NSW, Australia.
authors.forename: Barry
authors.initials: B
authors.lastname: Slobedman
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom js152@hermes.cam.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Sinclair
mesh_terms: D002478:Cells, Cultured; D054412:Chemokine CCL8 / Q000378:metabolism*; D003587:Cytomegalovirus / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000276:immunology / Q000821:virology; D014764:Viral Proteins / Q000378:metabolism*; D017735:Virus Latency
chemical_list: C515453:CCL8 protein, human; D054412:Chemokine CCL8; C508609:IL10 protein, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D014764:Viral Proteins; D016753:Interleukin-10