Bromodomain proteins regulate human cytomegalovirus latency and reactivation allowing epigenetic therapeutic intervention

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.