title: Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal.
abstract: Persistence of latently infected cells in presence of Anti-Retroviral Therapy presents the main obstacle to HIV-1 eradication. Much effort is thus placed on identification of compounds capable of HIV-1 latency reversal in order to render infected cells susceptible to viral cytopathic effects and immune clearance. We identified the BAF chromatin remodeling complex as a key player required for maintenance of HIV-1 latency, highlighting its potential as a molecular target for inhibition in latency reversal. Here, we screened a recently identified panel of small molecule inhibitors of BAF (BAFi's) for potential to activate latent HIV-1. Latency reversal was strongly induced by BAFi's Caffeic Acid Phenethyl Ester and Pyrimethamine, two molecules previously characterized for clinical application. BAFi's reversed HIV-1 latency in cell line based latency models, in two ex vivo infected primary cell models of latency, as well as in HIV-1 infected patient's CD4 + T cells, without inducing T cell proliferation or activation. BAFi-induced HIV-1 latency reversal was synergistically enhanced upon PKC pathway activation and HDAC-inhibition. Therefore BAFi's constitute a promising family of molecules for inclusion in therapeutic combinatorial HIV-1 latency reversal.
authors: Department of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The Netherlands.
authors: Mateusz
authors: M
authors: Stoszko
authors: Department of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The Netherlands.
authors: Elisa
authors: E
authors: De Crignis
authors: Department of Internal Medicine, Section of Infectious Diseases, Erasmus University Medical Center, PO Box 2040 3000CA, Rotterdam, The Netherlands.
authors: Casper
authors: C
authors: Rokx
authors: Department of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The Netherlands.
authors: Mir Mubashir
authors: MM
authors: Khalid
authors: Department of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The Netherlands.
authors: Cynthia
authors: C
authors: Lungu
authors: Department of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The Netherlands.
authors: Robert-Jan
authors: RJ
authors: Palstra
authors: Department of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The Netherlands.
authors: Tsung Wai
authors: TW
authors: Kan
authors: Department of Viroscience, Erasmus University Medical Center, PO Box 2040 3000CA, Rotterdam, the Netherlands.
authors: Charles
authors: C
authors: Boucher
authors: Department of Internal Medicine, Section of Infectious Diseases, Erasmus University Medical Center, PO Box 2040 3000CA, Rotterdam, The Netherlands.
authors: Annelies
authors: A
authors: Verbon
authors: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
authors: Emily C
authors: EC
authors: Dykhuizen
authors: Department of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The Netherlands. Electronic address: t.mahmoudi@erasmusmc.nl.
authors: Tokameh
authors: T
authors: Mahmoudi
mesh_terms: D000818:Animals; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055808:Drug Discovery; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014158:Transcription, Genetic; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
chemical_list: C501959:BANF1 protein, human; D015415:Biomarkers; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins
keywords: BAF complex; BAF, BRG-Brahma Associated Factors; BAF250a, BAF Associated Factor 250 a; BAFi, BAF inhibitor; BRG-1, Brahma Related Gene 1; CAPE, caffeic acid phenetyl esther; ChIP, Chromatin Immunoprecipitation; Chromatin remodeling; CycA, Cyclophilin A; DHS-1, DNase Hypersensitive Site 1; ES cells, embryonic stem cells; FAIRE, Formaldehyde Assisted Isolation of Regulatory Elements; FBS, Fetal Bovine Serum; GFP, Green Fluorescent Protein; HDAC, histone deacetylase; HIV; HIV-1, human immunodeficiency virus type 1; IFNß, Interferon beta; IL10, Interleukin 10; IL12, Interleukin 12; IL4, Interleukin 4; IL6, Interleukin 6; INI-1, Integrase Interactor 1; IRES, Internal Ribosome Entry Site; IκB-α, Inhibitor of NF-κB – alpha; LRA, latency reversal agent; LTR, Long Terminal Repeat; Latency; MIP26, Major Intrinsic Protein; MMP9, Matrix Metallopeptidase 9; NF-κB, Nuclear Factor Kappa-light-chain-enhancer of activated B cells; PBMC, peripheral blood mononuclear cell; PBS, Phosphate Buffered Saline; PKC, Protein Kinase C; PYR, Pyrimethamine; RT-qPCR, Reverse Transcriptase, quantitative Polymerase Chain Reaction; SAHA, Suberoylanilide Hydroxamic Acid; SD, Standard Deviation; SOCS3, Suppressor Of Cytokine Signaling 3; TGF-ß, Transforming Growth Factor beta; TLR2, Toll-like Receptor 2; bp, base pairs; cART, combination Antiretroviral Therapy; latency reversal agents; nuc, nucleosome; siRNA, small interfering RNA