Open AccessBromodomain proteins regulate human cytomegalovirus latency and reactivation allowing epigenetic therapeutic intervention
Author(s) -
Ian J. Groves,
Sarah Jackson,
Emma Poole,
Aharon Nachshon,
Batsheva Rozman,
Michal Schwartz,
Rab K. Prinjha,
David F. Tough,
John Sinclair,
Mark R. Wills
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2023025118
Subject(s) - bromodomain , human cytomegalovirus , lytic cycle , biology , brd4 , p tefb , virology , virus latency , epigenetics , cancer research , immunology , virus , gene expression , gene , viral replication , genetics , promoter
Significance Human cytomegalovirus (HCMV) reactivation is a major cause of posttransplant morbidity/mortality. One approach toward reducing this is purging the transplant donor and/or recipient of latently infected cells prior to stem-cell or organ harvest/engraftment. Our findings show the involvement of host bromodomain (BRD) proteins in regulation of HCMV latency and reactivation. Bromodomain and extra-terminal inhibitor (I-BET) treatment of latently infected cells causes reactivation of lytic gene expression by release of transcription activator P-TEFb (CDK9/CycT1) from BRD4-associated repressive complexes, with subsequent recruitment via host superelongation complex (SEC). This results in immune targeting and T cell-mediated killing of these otherwise latently infected cells and provides a therapeutic “shock and kill” strategy that could reduce HCMV-mediated disease in the transplant setting.