Inhibitors of Histone Deacetylases

Deacetylation of histone proteins at the HIV type 1 (HIV-1) long terminal repeat (LTR) by histone deactylases (HDACs) can promote transcriptional repression and virus latency. As such, HDAC inhibitors (HDACI) could be used to deplete reservoirs of persistent, quiescent HIV-1 proviral infection. However, the development of HDACI to purge latent HIV-1 requires knowledge of the HDAC isoforms contributing to viral latency and the development of inhibitors specific to these isoforms. In this study, we identify the HDACs responsible for HIV-1 latency in Jurkat J89GFP cells using a chemical approach that correlates HDACI isoform specificity with their ability to reactivate latent HIV-1 expression. We demonstrate that potent inhibition or knockdown of HDAC1, an HDAC isoform reported to drive HIV-1 into latency, was not sufficient to de-repress the viral LTR. Instead, we found that inhibition of HDAC3 was necessary to activate latent HIV-1. Consistent with this finding, we identified HDAC3 at the HIV-1 LTR by chromatin immunoprecipitation. Interestingly, we show that valproic acid is a weak inhibitor of HDAC3 (IC50 = 5.5 mm) relative to HDAC1 (IC50 = 170 μm). Because the total therapeutic concentration of valproic acid ranges from 275 to 700 μm in adults, these data may explain why this inhibitor has no effect on the decay of latent HIV reservoirs in patients. Taken together, our study suggests an important role for HDAC3 in HIV-1 latency and, importantly, describes a chemical approach that can readily be used to identify the HDAC isoforms that contribute to HIV-1 latency in other cell types.

• Publication year

  2011

• Venue

  Journal of Biological Chemistry

• Publication date

  2011-04-29

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M110.180224PMID 21531716PMCID PMC3121366
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Histone deacetylase inhibitor Scriptaid reactivates latent HIV-1 promoter by inducing histone modification in in vitro latency cell lines.

  2010cited by this paper
• Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands

  2010cited by this paper
• Antiretroviral Intensification and Valproic Acid Lack Sustained Effect on Residual HIV-1 Viremia or Resting CD4+ Cell Infection

  2010cited by this paper
• HIV–1 Infects Multipotent Progenitor Cells Causing Cell Death and Establishing Latent Cellular Reservoirs

  2010cited by this paper
• Mechanisms of HIV Latency: an Emerging Picture of Complexity

  2010cited by this paper
• HIV Persistence and the Prospect of Long-Term Drug-Free Remissions for HIV-Infected Individuals

  2010cited by this paper
• Synergistic Activation of HIV-1 Expression by Deacetylase Inhibitors and Prostratin: Implications for Treatment of Latent Infection

  2009cited by this paper
• The many roles of histone deacetylases in development and physiology: implications for disease and therapy

  2009cited by this paper
• Short communication: activation of latent HIV type 1 gene expression by suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor approved for use to treat cutaneous T cell lymphoma.

  2009cited by this paper
• A Limited Group of Class I Histone Deacetylases Acts To Repress Human Immunodeficiency Virus Type 1 Expression

  2009cited by this paper
• Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid

  2009cited by this paper
• Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

  2009cited by this paper
• Expression of latent human immunodeficiency type 1 is induced by novel and selective histone deacetylase inhibitors

  2009cited by this paper
• Suberoylanilide Hydroxamic Acid Reactivates HIV from Latently Infected Cells*

  2009cited by this paper
• "Shock and kill" effects of class I-selective histone deacetylase inhibitors in combination with the glutathione synthesis inhibitor buthionine sulfoximine in cell line models for HIV-1 quiescence

  2009cited by this paper
• Prolonged valproic acid treatment does not reduce the size of latent HIV reservoir

  2008cited by this paper
• Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells

  2008cited by this paper
• c-Myc and Sp1 Contribute to Proviral Latency by Recruiting Histone Deacetylase 1 to the Human Immunodeficiency Virus Type 1 Promoter

  2007cited by this paper
• Induction of chromosomally integrated HIV-1 LTR requires RBF-2 (USF/TFII-I) and RAS/MAPK signaling

  2007cited by this paper
• Recruitment of chromatin‐modifying enzymes by CTIP2 promotes HIV‐1 transcriptional silencing

  2007cited by this paper
• CBF‐1 promotes transcriptional silencing during the establishment of HIV‐1 latency

  2007cited by this paper
• Stability of the latent reservoir for HIV-1 in patients receiving valproic acid.

  2007cited by this paper
• NF‐κB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation

  2006cited by this paper
• Transcriptional Repression of Human Immunodeficiency Virus Type 1 by AP-4*

  2006cited by this paper
• Depletion of latent HIV-1 infection in vivo: a proof-of-concept study.

  2005cited by this paper
• Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors.

  2005cited by this paper
• Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression

  2004cited by this paper
• Direct and Quantitative Single-Cell Analysis of Human Immunodeficiency Virus Type 1 Reactivation from Latency

  2002cited by this paper
• The SMRT and N-CoR Corepressors Are Activating Cofactors for Histone Deacetylase 3

  2001cited by this paper
• Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

  2001cited by this paper
• The Human Factors YY1 and LSF Repress the Human Immunodeficiency Virus Type 1 Long Terminal Repeat via Recruitment of Histone Deacetylase 1

  2000cited by this paper
• HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression.

  1999cited by this paper
• Mutations in the tat Gene Are Responsible for Human Immunodeficiency Virus Type 1 Postintegration Latency in the U1 Cell Line

  1998cited by this paper
• Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

  1997cited by this paper
• Recovery of replication-competent HIV despite prolonged suppression of plasma viremia.

  1997cited by this paper
• Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy.

  1997cited by this paper
• A point mutation in the HIV-1 Tat responsive element is associated with postintegration latency.

  1996cited by this paper
• NF-κ B-Dependent and -Independent Pathways of HIV Activation in a Chronically Infected T Cell Line

  1994cited by this paper
• NF-kappa B-dependent and -independent pathways of HIV activation in a chronically infected T cell line.

  1994cited by this paper

• The effect of combining HIV latency reversal with inhibition of phosphoinositide-3 kinases or B-cell lymphoma-2 on the HIV reservoir

  2026cites this paper
• Lysine deacetylation inhibition reverses TDP-43 mislocalization and in combination with arimoclomol ameliorates neuromuscular pathology

  2025cites this paper
• Targeting HIV-1 transcription: road to a cure?

  2025cites this paper
• A TLR4/TRAF6-dependent signaling pathway mediates NCoR coactivator complex formation for inflammatory gene activation

  2024cites this paper
• Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum

  2024influential citation
• Advances in structure-activity relationships of HDAC inhibitors as HIV latency-reversing agents

  2024cites this paper
• HIV Expression in Infected T Cell Clones

  2024cites this paper
• Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy

  2023cites this paper
• Are inhibitors of histone deacetylase 8 (HDAC8) effective in hematological cancers especially acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)?

  2023cites this paper
• Evolution of Slow-Binding Inhibitors Targeting Histone Deacetylase Isoforms.

  2023cites this paper
• Luteotropic and Luteolytic Factors Modulate the Expression of Nuclear Receptor Coregulators in Bovine Luteal Cells Independently of Histone Acetyltransferase and Histone Deacetylase Activities

  2023influential citation
• Pharmacophore-based virtual screening, 3D QSAR, Docking, ADMET, and MD simulation studies: An in silico perspective for the identification of new potential HDAC3 inhibitors

  2023cites this paper
• Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites

  2023cites this paper
• Isoform-Selective Versus Nonselective Histone Deacetylase Inhibitors in HIV Latency Reversal

  2022cites this paper
• Forging a Functional Cure for HIV: Transcription Regulators and Inhibitors

  2022cites this paper
• Chasing a Breath of Fresh Air in Cystic Fibrosis (CF): Therapeutic Potential of Selective HDAC6 Inhibitors to Tackle Multiple Pathways in CF Pathophysiology

  2022cites this paper
• Toward a Functional Cure for HIV-1 Infection: The Block and Lock Therapeutic Approach

  2022cites this paper
• Non-Hydroxamate Zinc-Binding Groups as Warheads for Histone Deacetylases

  2021cites this paper
• Hallmarks of Retroelement Expression in T-Cells Treated With HDAC Inhibitors

  2021cites this paper
• In Vitro Pharmacokinetic/Pharmacodynamic Modeling of HIV Latency Reversal by Novel HDAC Inhibitors Using an Automated Platform

  2021cites this paper
• Histone Deacetylase Inhibitors as Therapeutic Interventions on Cervical Cancer Induced by Human Papillomavirus

  2021cites this paper
• Epigenetic Mechanisms of HIV-1 Persistence

  2021cites this paper
• Dissecting Histone Deacetylase 3 in Multiple Disease Conditions: Selective Inhibition as a Promising Therapeutic Strategy.

  2021cites this paper
• Short-chain fatty acids activate acetyltransferase p300

  2021cites this paper
• Discovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding Group.

  2020cites this paper
• Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice

  2020cites this paper
• Implantable HDAC-inhibiting chemotherapeutics derived from hydrophobic amino acids for localized anticancer therapy.

  2020cites this paper
• A novel chemical-combination screen in zebrafish identifies epigenetic small molecule candidates for the treatment of Duchenne muscular dystrophy

  2020cites this paper
• Dichotomous Engagement of HDAC3 Activity Governs Inflammatory Responses

  2020cites this paper
• A novel drug-combination screen in zebrafish identifies epigenetic small molecule candidates for Duchenne muscular dystrophy

  2020influential citation
• Drug Delivery System Targeting CD4+ T Cells for HIV-1 Latency Reactivation Towards the Viral Eradication.

  2020cites this paper
• Novel Histone Deacetylase Inhibitors and HIV-1 Latency-Reversing Agents Identified by Large-Scale Virtual Screening

  2020cites this paper
• Integrated Assessment of Viral Transcription, Antigen Presentation, and CD8+ T Cell Function Reveals Multiple Limitations of Class I-Selective Histone Deacetylase Inhibitors during HIV-1 Latency Reversal

  2020influential citation
• Histone deacetylase 6 inhibitor tubastatin A attenuates angiotensin II-induced hypertension by preventing cystathionine γ-lyase protein degradation.

  2019cites this paper
• Highly fluorescent and HDAC6 selective scriptaid analogues.

  2019cites this paper
• Role of APOBEC3 proteins in proteasome inhibitor-mediated reactivation of latent HIV-1 viruses.

  2019cites this paper
• Restoring T Cell Tolerance, Exploring the Potential of Histone Deacetylase Inhibitors for the Treatment of Juvenile Idiopathic Arthritis

  2019cites this paper
• Histone deacetylase inhibitors induce complex host responses that contribute to differential potencies of these compounds in HIV reactivation

  2019cites this paper
• Molecular Technology for Epigenetics Toward Drug Discovery

  2019cites this paper
• Identification of isoform-selective hydroxamic acid derivatives that potently reactivate HIV from latency

  2019cites this paper
• African Swine Fever Virus replication events and cell nucleus: new insights and perspectives.

  2019cites this paper
• From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs

  2019cites this paper
• Anti-angiogenic effects of valproic acid in a mouse model of oxygen-induced retinopathy.

  2018cites this paper
• Transcription: Insights From the HIV-1 Promoter.

  2018cites this paper
• Epigenetic metalloenzymes.

  2018cites this paper
• TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy

  2018cites this paper
• Elimination of HIV-1 Latently Infected Cells by Gnidimacrin and a Selective HDAC Inhibitor.

  2018cites this paper
• Workflow for defining reference chemicals for assessing performance of in vitro assays.

  2018cites this paper
• Inhibitors of Signaling Pathways That Block Reversal of HIV-1 Latency

  2018cites this paper
• HDAC3 Inhibition Promotes Alternative Activation of Macrophages but Does Not Affect Functional Recovery after Spinal Cord Injury

  2018cites this paper
• Trichostatin A inhibits deacetylation of histone H3 and p53 by SIRT6.

  2018cites this paper
• HDAC Inhibition Improves the Sarcoendoplasmic Reticulum Ca2+-ATPase Activity in Cardiac Myocytes

  2018cites this paper
• Cellular defence or viral assist: the dilemma of HDAC6.

  2017cites this paper
• Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

  2017cites this paper
• The Multifaceted Contributions of Chromatin to HIV-1 Integration, Transcription, and Latency.

  2017cites this paper
• Therapeutic strategies to fight HIV-1 latency: progress and challenges

  2017cites this paper
• Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation

  2017cites this paper
• "Drug" Discovery with the Help of Organic Chemistry.

  2017cites this paper
• Epigenetic regulation of the glucose transporter gene Slc2a1 by β‐hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice

  2017cites this paper
• Quercetin synergistically reactivates human immunodeficiency virus type 1 latency by activating nuclear factor‑κB.

  2017cites this paper
• Quiescence Promotes Latent HIV Infection and Resistance to Reactivation from Latency with Histone Deacetylase Inhibitors

  2017cites this paper
• Analysis of HDACi-Induced Changes in Chromosomal Passenger Complex Localization.

  2017cites this paper
• Scaffold dependent histone deacetylase (HDAC) inhibitor induced re-equilibration of the subcellular localization and post-translational modification state of class I HDACs

  2017cites this paper
• Sodium phenylbutyrate abrogates African swine fever virus replication by disrupting the virus-induced hypoacetylation status of histone H3K9/K14.

  2017cites this paper
• Future of Drug Discovery

  2017cites this paper
• Phenyl butyrate inhibits pyruvate dehydrogenase kinase 1 and contributes to its anti‐cancer effect

  2017cites this paper
• Selectivity and Kinetic Requirements of HDAC Inhibitors as Progranulin Enhancers for Treating Frontotemporal Dementia.

  2017cites this paper
• Impact of Nutrition on Healthy Aging

  2017cites this paper
• The Distinct Roles of Class I and II RPD3-Like Histone Deacetylases in Salinity Stress Response1[OPEN]

  2017cites this paper
• Targeting Class I Histone Deacetylases in a "Complex" Environment.

  2017cites this paper
• Hydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6

  2017cites this paper
• Combined Effect of Histone Acetylation and Acetyl Mark Readers on Radiation Sensitivity

  2016cites this paper
• Targeting Histone Deacetylases in Melanoma and T-cells to Improve Cancer Immunotherapy

  2016cites this paper
• Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends.

  2016cites this paper
• The Impact of External Factors on the Epigenome: In Utero and over Lifetime

  2016cites this paper
• TET3 Inhibits Type I IFN Production Independent of DNA Demethylation.

  2016cites this paper
• HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatin

  2016cites this paper
• Effects of heme arginate in HIV-1 acute infection and in latency reversal

  2016cites this paper
• Medicinal significance of naturally occurring cyclotetrapeptides

  2016cites this paper
• Class IIa histone deacetylases affect neuronal remodeling and functional outcome after stroke.

  2016cites this paper
• Impact of Chromatin on HIV Replication

  2015cites this paper
• Histone Deacetylase Inhibitor Romidepsin Inhibits De Novo HIV-1 Infections

  2015cites this paper
• A fluorescent histone deacetylase (HDAC) inhibitor for cellular imaging.

  2015cites this paper
• Discovery of a new class of histone deacetylase inhibitors with a novel zinc binding group.

  2015cites this paper
• AF4 and AF4-MLL mediate transcriptional elongation of 5-lipoxygenase mRNA by 1, 25-dihydroxyvitamin D3

  2015cites this paper
• Evaluation of histone deacetylase inhibitors (HDACi) as therapeutic leads for human African trypanosomiasis (HAT).

  2015cites this paper
• Oxamflatin Treatment Enhances Cloned Porcine Embryo Development and Nuclear Reprogramming

  2015cites this paper
• Therapeutic Approaches to Eradicate Latent HIV-1 in Resting CD4+ T Cells.

  2015cites this paper
• Targeting Selective Autophagy of Insoluble Protein Aggregates: The Sniper’s Philosophy

  2015cites this paper
• Understanding the Roles of Nuclear Receptors in the Maintenance of HIV Proviral Latency Using Novel Gene Editing Techonology

  2015cites this paper
• Epigenetic control of HIV-1 post integration latency: implications for therapy

  2015cites this paper
• Discovery of a Small Molecule Agonist of Phosphatidylinositol 3-Kinase p110α That Reactivates Latent HIV-1

  2014cites this paper
• Dissecting the Mechanism of Histone Deacetylase Inhibitors to Enhance the Activity of Zinc Finger Nucleases Delivered by Integrase-Defective Lentiviral Vectors

  2014cites this paper
• A novel action mechanism for MPT0G013, a derivative of arylsulfonamide, inhibits tumor angiogenesis through up-regulation of TIMP3 expression

  2014cites this paper
• Dilazep synergistically reactivates latent HIV-1 in latently infected cells Hanxian ZengSijie LiuPengfei WangXiying QuHaiyan Ji • Xiaohui WangXiaoli ZhuZhishuo SongXinyi YangZhongjun Ma •

  2014cites this paper
• Inhibition of histone deacetylase 4 increases cytotoxicity of docetaxel in gastric cancer cells

  2014cites this paper
• HIV-1 Latency: An Update of Molecular Mechanisms and Therapeutic Strategies

  2014cites this paper
• Selective HDAC Inhibition for the Disruption of Latent HIV-1 Infection

  2014cites this paper
• Remarks on the Conference HIV pathogenesis, virus versus host, Alberta, Canada, March 9-14, 2014

  2014cites this paper
• Study of Marine Natural Products Including Resorcyclic Acid Lactones from Humicola fuscoatra That Reactivate Latent HIV-1 Expression in an in Vitro Model of Central Memory CD4+ T Cells

  2014cites this paper