Didehydro-Cortistatin A Inhibits HIV-1 by Specifically Binding to the Unstructured Basic Region of Tat

Mediouni, Sonia; Chinthalapudi, Krishna; Ekka, Mary Krishna; Usui, Ippei; Jablonski, Joseph; Clementz, Mark A.; Mousseau, Guillaume; Nowak, J.; Macherla, Venkat R.; Beverage, Jacob N.; Esquenazi, Eduardo; Baran, Phil S.; Vera, Ian Mitchelle S. de; Kojetin, D.J.; Loret, Erwann; Nettles, Kendall; Maiti, Souvik; Izard, Tina; Valente, Susana T.

doi:10.1128/mbio.02662-18

Cited by 66 publications

(66 citation statements)

References 64 publications

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“…However, large-scale dCA production may be difficult [100], which could limit its availability. As the molecular interaction between dCA and Tat has been modeled [74], a future in silico screening project using pharmacophore based models of dCA interaction with Tat may identify additional agents with anti-Tat activity. Drug repurposing of the rheumatoid arthritis drug triptolide as an HIV inhibitor awaits safety and efficacy outcomes in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

“…dCA also specifically bound to the basic domain of HIV-2 Tat [73] and SIV Tat [76]. The binding of dCA to the basic domain of Tat occurred across HIV subtypes A to E in the main group M [104], but dCA did not bind to the basic domain of Rev and HEXIM1 [74]. dCA caused a redistribution of Tat in the nucleus from the nucleolus to the nucleoplasm and periphery of the nucleolus in a dose-dependent manner [73].…”

Section: Two Compounds That Inhibit Tat Activitymentioning

confidence: 99%

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Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure

Jin

Lin

et al. 2020

Viruses

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The human immunodeficiency virus type 1 (HIV) establishes a chronic infection that can be well controlled, but not cured, by combined antiretroviral therapy (cART). Interventions have been explored to accomplish a functional cure, meaning that a patient remains infected but HIV is undetectable in the blood, with the aim of allowing patients to live without cART. Tat, the viral transactivator of transcription protein, plays a critical role in controlling HIV transcription, latency, and viral rebound following the interruption of cART treatment. Therefore, a logical approach for controlling HIV would be to block Tat. Tackling Tat with inhibitors has been a difficult task, but some recent discoveries hold promise. Two anti-HIV proteins, Nullbasic (a mutant of Tat) and HT1 (a fusion of HEXIM1 and Tat functional domains) inhibit viral transcription by interfering with the interaction of Tat and cellular factors. Two small molecules, didehydro-cortistatin A (dCA) and triptolide, inhibit Tat by different mechanisms: dCA through direct binding and triptolide through enhanced proteasomal degradation. Finally, two Tat-based vaccines under development elicit Tat-neutralizing antibodies. These vaccines have increased the levels of CD4+ cells and reduced viral loads in HIV-infected people, suggesting that the new vaccines are therapeutic. This review summarizes recent developments of anti-Tat agents and how they could contribute to a functional cure for HIV.

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Section: Discussionmentioning

confidence: 99%

Section: Two Compounds That Inhibit Tat Activitymentioning

confidence: 99%

Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure

Jin

Lin

et al. 2020

Viruses

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“…On the other hand, the kinase module (composed of two subunits Med12 and Med13 and the kinase CDK8, or its paralog CDK19) are thought to be dispensable for HIV-1 transcription [136]. This is evidenced by small molecule inhibition or knockdown of these proteins in cell line models of HIV-1 latency [138,139]. Additional research would benefit our understanding of the role of mediator in HIV-1 PIC formation, initiation and elongation, particularly in biologically relevant systems such as primary CD4 + T cells.…”

Section: Early Stages Of Transcriptionmentioning

confidence: 99%

“…CDK8 generally plays a suppressive role as part of the mediator complex, though it is known to activate transcription of certain cellular genes [150]. Importantly, it was recently demonstrated that knockdown of CDK8 (and its paralog CDK19) had no effect on HIV-1 transcription [138,139]. CDK12/CDK13 has been shown to be involved in Ser2 phosphorylation towards the midpoint and 3' ends of genes, and play a role in RNA processing and splicing [143,151,152].…”

Section: Early Stages Of Transcriptionmentioning

confidence: 99%

Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure

Mori¹,

Valente²

2020

Viruses

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HIV-1 establishes a life-long infection when proviral DNA integrates into the host genome. The provirus can then either actively transcribe RNA or enter a latent state, without viral production. The switch between these two states is governed in great part by the viral protein, Tat, which promotes RNA transcript elongation. Latency is also influenced by the availability of host transcription factors, integration site, and the surrounding chromatin environment. The latent reservoir is established in the first few days of infection and serves as the source of viral rebound upon treatment interruption. Despite effective suppression of HIV-1 replication by antiretroviral therapy (ART), to below the detection limit, ART is ineffective at reducing the latent reservoir size. Elimination of this reservoir has become a major goal of the HIV-1 cure field. However, aside from the ideal total HIV-1 eradication from the host genome, an HIV-1 remission or functional cure is probably more realistic. The “block-and-lock” approach aims at the transcriptional silencing of the viral reservoir, to render suppressed HIV-1 promoters extremely difficult to reactivate from latency. There are unfortunately no clinically available HIV-1 specific transcriptional inhibitors. Understanding the mechanisms that regulate latency is expected to provide novel targets to be explored in cure approaches.

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“…We next investigated whether dCA binds the basic domain of SIV mac 239 Tat, as it does for HIV Tat (19,37). A biotinylated version of dCA, which has similar IC 50 against HIV than dCA (19), was used for pull-down assays, in combination with streptavidin-coated beads of transfected Tat proteins.…”

Section: Dca Binds To Siv Tat Basic Domainmentioning

confidence: 99%

The Tat inhibitor didehydro‐cortistatin A suppresses SIV replication and reactivation

et al. 2019

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The HIV‐1 transactivation protein (Tat) binds the HIV mRNA transactivation responsive element (TAR), regulating transcription and reactivation from latency. Drugs against Tat are unfortunately not clinically available. We reported that didehydro‐cortistatin A (dCA) inhibits HIV‐1 Tat activity. In human CD4+ T cells isolated from aviremic individuals and in the humanized mouse model of latency, combining dCA with antiretroviral therapy accelerates HIV‐1 suppression and delays viral rebound upon treatment interruption. This drug class is amenable to block‐and‐lock functional cure approaches, aimed at a durable state of latency. Simian immunodeficiency virus (SIV) infection of rhesus macaques (RhMs) is the best‐characterized model for AIDS research. Here, we demonstrate, using in vitro and cell‐based assays, that dCA directly binds to SIV Tat's basic domain. dCA specifically inhibits SIV Tat binding to TAR, but not a Tat‐Rev fusion protein, which activates transcription when Rev binds to its cognate RNA binding site replacing the apical region of TAR. Tat‐TAR inhibition results in loss of RNA polymerase II recruitment to the SIV promoter. Importantly, dCA potently inhibits SIV reactivation from latently infected Hut78 cells and from primary CD4+ T cells explanted from SIVmac239‐infected RhMs. In sum, dCA's remarkable breadth of activity encourages SIV‐infected RhM use for dCA preclinical evaluation.—Mediouni, S., Kessing, C. F., Jablonski, J. A., Thenin‐Houssier, S., Clementz, M., Kovach, M. D., Mousseau, G., de Vera, I.M.S., Li, C., Kojetin, D. J., Evans, D. T., Valente, S. T. The Tat inhibitor didehydro‐cortistatin A suppresses SIV replication and reactivation. FASEB J. 33, 8280–8293 (2019). http://www.fasebj.org

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Didehydro-Cortistatin A Inhibits HIV-1 by Specifically Binding to the Unstructured Basic Region of Tat

Cited by 66 publications

References 64 publications

Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure

Tat-Based Therapies as an Adjuvant for an HIV-1 Functional Cure

Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure

The Tat inhibitor didehydro‐cortistatin A suppresses SIV replication and reactivation

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