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.
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Authors
Lau, Betty
Van Damme, Ellen
Bunkens, Lieve
Sowash, Madeleine
King, Harry
Murphy, Eain
Van Loock, Marnix
Publication Date
2016-09Journal Title
J Gen Virol
ISSN
0022-1317
Publisher
Microbiology Society
Language
English
Type
Article
This Version
AM
Metadata
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Lau, B., Poole, E., Van Damme, E., Bunkens, L., Sowash, M., King, H., Murphy, E., et al. (2016). 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.. J Gen Virol https://doi.org/10.1099/jgv.0.000546
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.
Sponsorship
Medical Research Council (Grant ID: G:0701279); National Institute for Health Research Biomedical Research Centre
Funder references
Medical Research Council (MR/K021087/1)
Medical Research Council (G0701279)
Identifiers
External DOI: https://doi.org/10.1099/jgv.0.000546
This record's URL: https://www.repository.cam.ac.uk/handle/1810/257348
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