The bromodomain and extraterminal domain inhibitor bromosporine synergistically reactivates latent HIV-1 in latently infected cells

Pan, Hongda; Lu, Panpan; Shen, Yinzhong; Wang, Yanan; Jiang, Zhen; Yang, Xinyi; Zhong, Yangcheng; Yang, Haiwei; Khan, Inam Ulla; Zhou, Muya; Li, Bokang; Zhang, Ziyu; Xu, Jianqing; Lu, Hongzhou; Zhu, Huanzhang

doi:10.18632/oncotarget.21585

Cited by 10 publications

(11 citation statements)

References 53 publications

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“…Inhibition of either cyclin-dependent kinase (CDK) 2 or CDK9 has been reported to suppress HIV-1 transcription or replication in vitro or in vivo(36-41). Previous reports show that bromodomain inhibitors induced reactivation of HIV-1 latency is dependent on CDK9 (24, 25). HIV-1 replication, in CDK2-knockdown macrophages-like cells derived from pluripotent stem cells, was significantly reduced(42).…”

Section: Resultsmentioning

confidence: 93%

“…It is known that bromodomain-containing protein 4 (BRD4) competes P-TEFb and disrupts the interaction between Tat and P-TEFb, and forfeits the ability of Tat to trans-activate HIV-1 transcription(23-25). Given the important role of P-TEFb in regulating HIV gene expression, different BETi have been explored and tested to activate HIV-1 gene expression in latent models of primary CD4 + T cells, lymphocytic T cell lines and monocytic cell lines (26, 27).…”

Section: Introductionmentioning

confidence: 99%

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Specific activation of HIV-1 from monocytic reservoir cells by bromodomain inhibitor in humanized mice in vivo

Zhang²,

Reszka-Blanco

et al. 2018

Preprint

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Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Specific activation of HIV-1 from monocytic reservoir cells by bromodomain inhibitor in humanized mice in vivo

Zhang²,

Reszka-Blanco

et al. 2018

Preprint

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“…As previously reported, inhibition of either cyclin-dependent kinase 2 (CDK2) or CDK9 suppresses HIV-1 transcription or replication (40)(41)(42)(43)(44)(45), and bromodomain inhibitor-induced reactivation of HIV-1 latency is dependent on CDK9 (30,31). In CDK2 knockdown macrophage-like cells derived from pluripotent stem cells, HIV-1 replication is significantly reduced (46).…”

Section: I-bet151 Activates Hiv-1 Gene Expression In Monocytic Cells mentioning

confidence: 81%

Specific ActivationIn Vivoof HIV-1 by a Bromodomain Inhibitor from Monocytic Cells in Humanized Mice under Antiretroviral Therapy

Zhang

Reszka-Blanco

et al. 2019

J Virol

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Combination antiretroviral therapy (cART) effectively suppresses HIV-1 replication and enables HIV‑infected individuals to live long, productive lives. However, the persistence of HIV-1 reservoirs of both T and myeloid cells with latent or low-replicating HIV-1 in patients under cART makes HIV-1 infection an incurable disease. Recent studies have focused on the development of strategies to activate and purge these reservoirs. Bromodomain and extraterminal domain proteins (BETs) are epigenetic readers involved in modulating gene expression. Several bromodomain inhibitors (BETi) are reported to activate viral transcription in vitro in HIV-1 latency cell lines in a P-TEFb (CDK9/cyclin T1)-dependent manner. Little is known about BETi efficacy in activating HIV-1 reservoir cells under cART in vivo. Here we report that a BETi (I-BET151) efficiently activated HIV-1 reservoirs under effective cART in humanized mice in vivo. Interestingly, I-BET151 during suppressive cART in vivo activated HIV-1 gene expression only in monocytic cells and not in CD4+ T cells. We further demonstrate that BETi preferentially enhanced HIV-1 gene expression in monocytic cells rather than in T cells and that whereas CDK9 was involved in activating HIV-1 by I-BET151 in both monocytic and T cells, CDK2 enhanced HIV-1 transcription in monocytic cells but inhibited it in T cells. Our findings reveal a role for CDK2 in differential modulation of HIV-1 gene expression in myeloid cells and in T cells and provide a novel strategy to reactivate monocytic reservoirs with BETi during cART. IMPORTANCE Bromodomain inhibitors have been reported to activate HIV-1 transcription in vitro, but their effect on activation of HIV-1 reservoirs during cART in vivo is unclear. We found that BETi (I-BET151) treatment reactivated HIV-1 gene expression in humanized mice during suppressive cART. Interestingly, I-BET151 preferentially reactivated HIV-1 gene expression in monocytic cells, but not in CD4 T cells, in cART-treated mice. Furthermore, I-BET151 significantly increased HIV-1 transcription in monocytic cells, but not in HIV-1-infected CD4 T cells, via CDK2-dependent mechanisms. Our findings suggest that BETi can preferentially activate monocytic HIV-1 reservoir cells and that a combination of reservoir activation agents targeting different cell types and pathways is needed to achieve reactivation of different HIV-1 reservoir cells during cART.

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“…and LSF (39)(40)(41)(42). Likewise, the two identified inhibitors of BRD containing proteins, bromosporine and CPI-203, which target amongst others BRD4, which has been associated with the repressive SWI/SNF chromatin remodeling machinery (43), have been shown to efficiently reverse latency (33,34). Interestingly, both within this study newly discovered LRAs, SR-4370 and HPOB, target contrarily to the other four compounds, also the cytosolic deacetylase HDAC6, which has been found to be In conclusion, the described simplified screening for latency reversing agents in combination with an epigenetic-active drug library verified former studies and revealed two novel compounds, which may be used to induce HIV transcription in a broad range of latent viral reservoirs.…”

Section: Determination Of T-cell Activation and Side-effects On Othermentioning

confidence: 99%

Epigenetic compound screening uncovers small molecules for re-activation of latent HIV-1

Zutz¹,

Chen²,

Sippl³

et al. 2020

Preprint

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During infection with the human immunodeficiency virus type 1 (HIV-1), latent reservoirs are established, which circumvent full eradication of the virus by antiretroviral therapy (ART) and are the source for viral rebound after cessation of therapy. As these reservoirs are phenotypically undistinguishable from infected cells, current strategies aim to reactivate these reservoirs, followed by pharmaceutical and immunological destruction of the cells.Here, we employed a simple and convenient cell-based reporter system, which enables sample handling under biosafety level (BSL)-1 conditions, to screen for compounds that were able to reactivate latent HIV-1. The assay showed a high dynamic signal range and reproducibility with an average Z-factor of 0.77, classifying the system as robust. The assay was used for high-throughput screening (HTS) of an epigenetic compound library in combination with titration and cell-toxicity studies and revealed several potential new latency reversing agents (LRAs). Further validation in well-known latency model systems verified earlier studies and identified two novel compounds with very high reactivation efficiency and low toxicity. Both drugs, namely N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) and 2',3'-difluoro-[1,1'-biphenyl]-4-carboxylic acid, 2-butylhydrazide (SR-4370), showed comparable performances to other already known LRAs, did not activate CD4+ T-cells or caused changes in the composition of PBMCs as shown by flow cytometry analyses.Both compounds may represent an effective new treatment possibility for revocation of latency in HIV-1 infected individuals.

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The bromodomain and extraterminal domain inhibitor bromosporine synergistically reactivates latent HIV-1 in latently infected cells

Cited by 10 publications

References 53 publications

Specific activation of HIV-1 from monocytic reservoir cells by bromodomain inhibitor in humanized mice in vivo

Specific activation of HIV-1 from monocytic reservoir cells by bromodomain inhibitor in humanized mice in vivo

Specific ActivationIn Vivoof HIV-1 by a Bromodomain Inhibitor from Monocytic Cells in Humanized Mice under Antiretroviral Therapy

Epigenetic compound screening uncovers small molecules for re-activation of latent HIV-1

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