Bromodomain Inhibitors as Therapeutics for Herpesvirus-Related Disease: All BETs Are Off?

Groves, Ian J.; Wills, Mark R.

doi:10.3389/fcimb.2020.00329

Cited by 13 publications

(16 citation statements)

References 63 publications

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“…This view is comparable with observations using Epstein-Barr virus (EBV), which showed that treatment with the I-BET JQ1 during lytic EBV infection limited the virus life cycle in two ways: preventing expression of the EBV IE protein BZLF1 but also inhibiting interaction of BRD4 with the origin of lytic replication (oriLyt) ( 53 ), consistent with our use of the BRD4-degrader dBET1. Thus, despite possible different mechanisms, the restriction of HCMV reactivation by I-BETs might allow safer treatment of already immunocompromised patients ( 24 ). Cotreatment with GSK726 and CHR-4487 still induced reactivation and virus replication, likely due to HDACis aiding virus DNA replication.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we show that continuous treatment of latently infected cells with certain HDACis causes not just activation of HCMV gene expression but full reactivation and lytic cascade of the virus. In contrast, through the release of the cellular transcriptional activating complex positive-transcription elongation factor-b (P-TEFb) from repressive BRD4-associated aggregates, and recruitment via the superelongation complex (SEC) to viral promoters, inhibitors of the BET family of bromodomain (BRD)-containing histone acetylation mark reader proteins (I-BETs) ( 24 , 25 ) induce dysregulated HCMV gene expression. This allows production of virus lytic immunogens, including immunodominant IE72, pp65, and gB, while restricting the expression of many viral immunomodulating proteins (e.g., MHC class I/II downmodulators US2, 3, 6, 8, and 11) and, most importantly, virus DNA replication machinery (e.g., UL44, UL112).…”

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confidence: 99%

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

Groves

Jackson

Poole

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Groves

Jackson

Poole

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Due to the fact that the bromodomain-containing proteins act as epigenetic modulators controlling both cellular functions and the viral life cycle (19) their targeting (especially the targeting of BRD4) via small molecule inhibitors has emerged as a potent therapy for viral infectious diseases (19,23,50,54,60).…”

Section: Discussionmentioning

confidence: 99%

“…The severe acute respiratory syndrome-coronavirus (SARS-CoV-2) emerged in China at the end of December 2019. Globally, as of 19 th January, 2021 there have been 94.124.612 confirmed cases of the coronavirus disease 2019 (COVID- 19), including 929.994 deaths reported to WHO (https://covid19.who.int/). The clinical presentation of COVID-19 is diverse, ranging from asymptomatic infection to mild upper respiratory tract illness to severe interstitial pneumonia with respiratory failure and death (31).…”

Section: Introductionmentioning

confidence: 99%

In silico investigation of the viroporin E as a vaccine target against SARS-CoV-2

Rouka

Gourgoulianis

Zarogiannis

2021

American Journal of Physiology-Lung Cellular and Molecular Phys

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Viroporins, integral viral membrane ion channel proteins, interact with host-cell proteins deregulating physiological processes and activating inflammasomes. Severity of COVID-19 might be associated with hyperinflammation, thus we aimed at the complete immunoinformatic analysis of the SARS-CoV-2 viroporin E, P0DTC4. We also identified the human proteins interacting with P0DTC4 and the enriched molecular functions of the corresponding genes. The complete sequence of P0DTC4 in FASTA format was processed in 10 databases relative to secondary and tertiary protein structure analyses and prediction of optimal vaccine epitopes. Three more databases were accessed for the retrieval and the molecular functional characterization of the P0DTC4 human interactors. The immunoinformatics analysis resulted in the identification of 4 discontinuous B-cell epitopes along with 1 linear B-cell epitope and 11 T-cell epitopes which were found to be antigenic, immunogenic, non-allergen, non-toxin and unable to induce autoimmunity thus fulfilling prerequisites for vaccine design. The functional enrichment analysis showed that the predicted host interactors of P0DTC4 target the cellular acetylation network. Two of the identified host-cell proteins-BRD2 and BRD4- have been shown to be promising targets for anti-viral therapy. Thus, our findings have implications for COVID-19 therapy and indicate that viroporin E could serve as a promising vaccine target against SARS-CoV-2. Validation experiments are required to complement these in-silico results.

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“…Alternatively, the “block and lock” paradigm aims to push latent HIV reservoirs into tight latency through inhibition of Tat-dependent transcription [ 17 , 174 ]. Epigenetic drugs have also been tested in the context of other chronic viral infections, such as in the use of bromodomain and extra-terminal domain (BET) inhibitors to target HPV and herpesvirus infections [ 175 , 176 ]. Similarly, inhibitors of lysine-specific histone demethylase 1 (LSD1) and PRC2 enzymatic subunit EZH2 have been shown to blunt HSV-1 reactivation [ 98 , 177 , 178 ].…”

Section: Outlook For Epigenetic-directed Therapeutic Interventions For Viral Infectionsmentioning

confidence: 99%

Clinical Manifestations and Epigenetic Regulation of Oral Herpesvirus Infections

Atyeo

Rodriguez

Papp

et al. 2021

Viruses

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The oral cavity is often the first site where viruses interact with the human body. The oral epithelium is a major site of viral entry, replication and spread to other cell types, where chronic infection can be established. In addition, saliva has been shown as a primary route of person-to-person transmission for many viruses. From a clinical perspective, viral infection can lead to several oral manifestations, ranging from common intraoral lesions to tumors. Despite the clinical and biological relevance of initial oral infection, little is known about the mechanism of regulation of the viral life cycle in the oral cavity. Several viruses utilize host epigenetic machinery to promote their own life cycle. Importantly, viral hijacking of host chromatin-modifying enzymes can also lead to the dysregulation of host factors and in the case of oncogenic viruses may ultimately play a role in promoting tumorigenesis. Given the known roles of epigenetic regulation of viral infection, epigenetic-targeted antiviral therapy has been recently explored as a therapeutic option for chronic viral infection. In this review, we highlight three herpesviruses with known roles in oral infection, including herpes simplex virus type 1, Epstein–Barr virus and Kaposi’s sarcoma-associated herpesvirus. We focus on the respective oral clinical manifestations of these viruses and their epigenetic regulation, with a specific emphasis on the viral life cycle in the oral epithelium.

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Bromodomain Inhibitors as Therapeutics for Herpesvirus-Related Disease: All BETs Are Off?

Cited by 13 publications

References 63 publications

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

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

In silico investigation of the viroporin E as a vaccine target against SARS-CoV-2

Clinical Manifestations and Epigenetic Regulation of Oral Herpesvirus Infections

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