Abstract
Reactivation of human cytomegalovirus (HCMV) from latency is a major health consideration for recipients of stem-cell and solid organ transplantations. With over 200,000 transplants taking place globally per annum, virus reactivation can occur in more than 50% of cases leading to loss of grafts as well as serious morbidity and even mortality. Here, we present the most extensive screening to date of epigenetic inhibitors on HCMV latently infected cells and find that histone deacetylase inhibitors (HDACis) and bromodomain inhibitors are broadly effective at inducing virus immediate early gene expression. However, while HDACis, such as myeloid-selective CHR-4487, lead to production of infectious virions, inhibitors of bromodomain (BRD) and extraterminal proteins (I-BETs), including GSK726, restrict full reactivation. Mechanistically, we show that BET proteins (BRDs) are pivotally connected to regulation of HCMV latency and reactivation. Through BRD4 interaction, the transcriptional activator complex P-TEFb (CDK9/CycT1) is sequestered by repressive complexes during HCMV latency. Consequently, I-BETs allow release of P-TEFb and subsequent recruitment to promoters via the superelongation complex (SEC), inducing transcription of HCMV lytic genes encoding immunogenic antigens from otherwise latently infected cells. Surprisingly, this occurs without inducing many viral immunoevasins and, importantly, while also restricting viral DNA replication and full HCMV reactivation. Therefore, this pattern of HCMV transcriptional dysregulation allows effective cytotoxic immune targeting and killing of latently infected cells, thus reducing the latent virus genome load. This approach could be safely used to pre-emptively purge the virus latent reservoir prior to transplantation, thereby reducing HCMV reactivation-related morbidity and mortality.
Original language | English |
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Article number | e2023025118 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 118 |
Issue number | 9 |
DOIs | |
State | Published - 2 Mar 2021 |
Externally published | Yes |
Bibliographical note
Funding Information:A.N., B.R., and M.S. are members of Noam Stern-Ginossar's laboratory, whom we thank for RNA-seq technical assistance. R.K.P. is Vice-President, Head of Adaptive Immunity and Immuno-epigenetics Research Unit, and D.F.T. is a Senior Fellow, Senior Scientific Director of the Adaptive Immunity Research Unit, GlaxoSmithKline. This research was supported by the Cambridge National Institute for Health Research Biomedical Research Centre (NIHR BRC) Cell Phenotyping Hub. In particular, we thank Nika Romashova for advice and support. M.R.W. and J.H.S. are funded by the British Medical Research Council (Grant MR/S00081X/1) and a GSK-Varsity Initiative award (to M.R.W. and J.H.S.).
Funding Information:
ACKNOWLEDGMENTS. A.N., B.R., and M.S. are members of Noam Stern-Ginossar’s laboratory, whom we thank for RNA-seq technical assistance. R.K.P. is Vice-President, Head of Adaptive Immunity and Immuno-epigenetics Research Unit, and D.F.T. is a Senior Fellow, Senior Scientific Director of the Adaptive Immunity Research Unit, GlaxoSmithKline. This research was supported by the Cambridge National Institute for Health Research Biomedical Research Centre (NIHR BRC) Cell Phenotyping Hub. In particular, we thank Nika Romashova for advice and support. M.R.W. and J.H.S. are funded by the British Medical Research Council (Grant MR/S00081X/1) and a GSK-Varsity Initiative award (to M.R.W. and J.H.S.).
Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.
Keywords
- Bromodomain proteins
- Cytomegalovirus
- Epigenetics
- I-BET
- Latency