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dc.contributor.authorPoole, Emmaen
dc.contributor.authorCarlan da Silva, Maria Cristinaen
dc.contributor.authorHuang, Chrisen
dc.contributor.authorPerera, Marianneen
dc.contributor.authorJackson, Sarahen
dc.contributor.authorGroves, Ianen
dc.contributor.authorWills, Marken
dc.contributor.authorRana, Ameren
dc.contributor.authorSinclair, Johnen
dc.date.accessioned2021-05-05T23:30:15Z
dc.date.available2021-05-05T23:30:15Z
dc.date.issued2021-06en
dc.identifier.issn2150-7511
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/322003
dc.description.abstractHuman cytomegalovirus (HCMV) presents a major health burden in the immunocompromised and in stem cell transplant medicine. A lack of understanding about the mechanisms of HCMV latency in undifferentiated CD34+ stem cells, and how latency is broken for the virus to enter the lytic phase of its infective cycle, has hampered the development of essential therapeutics. Using a human induced pluripotent stem cell (iPSC) model of HCMV latency and patient-derived myeloid cell progenitors, we demonstrate that bone morphogenetic protein receptor type 2 (BMPR2) is necessary for HCMV latency. In addition, we define a crucial role for the transcription factor Yin Yang 1 (YY1) in HCMV latency; high levels of YY1 are maintained in latently infected cells as a result of BMPR2 signaling through the SMAD4/SMAD6 axis. Activation of SMAD4/6, through BMPR2, inhibits TGFbeta receptor signaling, which leads to the degradation of YY1 via induction of a cellular microRNA (miRNA), hsa-miR-29a. Pharmacological targeting of BMPR2 in progenitor cells results in the degradation of YY1 and an inability to maintain latency and renders cells susceptible to T cell killing. These data argue that BMPR2 plays a role in HCMV latency and is a new potential therapeutic target for maintaining or disrupting HCMV latency in myeloid progenitors. IMPORTANCE Understanding the mechanisms which regulate HCMV latency could allow therapeutic targeting of the latent virus reservoir from where virus reactivation can cause severe disease. We show that the BMPR2/TGFbeta receptor/YY1 signaling axis is crucial to maintain HCMV latency in undifferentiated cells and that pharmacological reduction of BMPR2 in latently infected cells leads to reactivation of the viral lytic transcription program, which renders the infected cell open to immune detection and clearance in infected individuals. Therefore, this work identifies key host-virus interactions which regulate HCMV latent infection. It also demonstrates a potential new therapeutic approach to reduce HCMV reactivation-mediated disease by the treatment of donor stem cells/organs prior to transplantation, which could have a major impact in the transplant disease setting.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleA BMPR2/YY1 Signaling Axis Is Required for Human Cytomegalovirus Latency in Undifferentiated Myeloid Cells.en
dc.typeArticle
prism.issueIdentifier3en
prism.publicationDate2021en
prism.publicationNamemBioen
prism.startingPagee0022721
prism.volume12en
dc.identifier.doi10.17863/CAM.69461
dcterms.dateAccepted2021-04-28en
rioxxterms.versionofrecord10.1128/mbio.00227-21en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2021-06en
dc.contributor.orcidPoole, Emma [0000-0003-3904-6121]
dc.contributor.orcidJackson, Sarah [0000-0002-4230-9220]
dc.contributor.orcidGroves, Ian [0000-0001-8882-6701]
dc.contributor.orcidWills, Mark [0000-0001-8548-5729]
dc.contributor.orcidSinclair, John [0000-0002-2616-9571]
dc.identifier.eissn2150-7511
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/S00081X/1)
pubs.funder-project-idMRC (MR/K021087/1)
pubs.funder-project-idBritish Heart Foundation (PG/14/31/30786)
pubs.funder-project-idBritish Heart Foundation (SP/12/12/29836)
cam.orpheus.successMon Jun 14 07:30:30 BST 2021 - The item has an open VoR version.*
cam.orpheus.counter5*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International