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

ABSTRACT: We report the application of RNA sequencing technology for high-throughput profiling of both host and human cytomegalovirus (HCMV) transcript levels in latenly infected CD14+ monocytes after treatment with histone deacetylase inhibitors (CHR-4487) and BET-bromodomain inhibitors (GSK726).

ORGANISM(S): Homo sapiens

PROVIDER: GSE156169 | GEO | 2021/02/11

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC7936348 | biostudies-literature

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

Project description:Bromodomain proteins regulate human cytomegalovirus latency and reactivation allowing epigenetic therapeutic intervention.

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Profiling the blood compartment of Hematopoietic Stem Cell Transplant patients during Human Cytomegalovirus reactivation

Project description:Human cytomegalovirus (HCMV) reactivation is a leading infectious cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT) patients. HCMV reactivation is characterized by detection of viral DNA in the blood (DNAemia), however, the role of the blood compartment during HCMV reactivation is not well characterized. Using powerful molecular tools, we characterized HCMV infection in Peripheral Blood Mononuclear Cells (PBMCs) during DNAemia in HCMV reactivating HSCT patients. Surprisingly we found that all PBMC populations harbored extremely low levels of viral DNA and extremely low levels of viral transcripts. Remarkably, the viral transcripts detected in these samples were mainly immediate early genes indicating that these cells do not go through a full productive cycle. Analysis of the cellular transcriptome revealed characteristic transcriptional changes in high DNAemic samples implying the development of HCMV-specific T cells and inhibition of regulatory T cell function. Overall, our data indicate that DNAemia in HCMV reactivating HSCT patients is associated with distinct immune signatures but is not necessarily accompanied by substantial infection of PBMCs, and that PBMCs are not productively infected. These findings are important for understanding the role of the blood compartment in progression and control of HCMV during reactivation.

2020-11-18 | GSE161752 | GEO

Defining the Transcriptional Landscape during Cytomegalovirus Latency with Single-Cell RNA Sequencing

Project description:Primary infection with human cytomegalovirus (HCMV) results in a lifelong infection due to its ability to establish latent infection, with one characterized viral reservoir being hematopoietic cells. Although reactivation from latency causes serious disease in immunocompromised individuals, our molecular understanding of latency is limited. Here, we delineate viral gene expression during natural HCMV persistent infection by analyzing the massive transcriptome sequencing (RNA-seq) atlas generated by the Genotype-Tissue Expression (GTEx) project. This systematic analysis reveals that HCMV persistence in vivo is prevalent in diverse tissues. Notably, we find only viral transcripts that resemble gene expression during various stages of lytic infection with no evidence of any highly restricted latency-associated viral gene expression program. To further define the transcriptional landscape during HCMV latent infection, we also used single-cell RNA-seq and a tractable experimental latency model. In contrast to some current views on latency, we also find no evidence for any highly restricted latency-associated viral gene expression program. Instead, we reveal that latency-associated gene expression largely mirrors a late lytic viral program, albeit at much lower levels of expression. Overall, our work has the potential to revolutionize our understanding of HCMV persistence and suggests that latency is governed mainly by quantitative changes, with a limited number of qualitative changes, in viral gene expression.

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Global reprogramming of the cellular translational landscape facilitates cytomegalovirus replication

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Global reprogramming of the cellular translational landscape facilitates cytomegalovirus replication

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Epigenetically repressing human cytomegalovirus lytic infection and reactivation from latency in THP-1 model by targeting H3K9 and H3K27 histone demethylases

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