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EBioMedicine. 2015 Nov 27;3:108-121. doi: 10.1016/j.ebiom.2015.11.047. eCollection 2016 Jan.

Small Molecule Inhibitors of BAF; A Promising Family of Compounds in HIV-1 Latency Reversal.

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Department of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The Netherlands.
Department of Internal Medicine, Section of Infectious Diseases, Erasmus University Medical Center, PO Box 2040 3000CA, Rotterdam, The Netherlands.
Department of Viroscience, Erasmus University Medical Center, PO Box 2040 3000CA, Rotterdam, the Netherlands.
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA.
Department of Biochemistry, Erasmus University Medical Center, Ee634, PO Box 2040 3000CA, Rotterdam, The Netherlands. Electronic address:


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.


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

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