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

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

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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism
  • Drug Discovery*
  • Gene Expression Regulation, Viral / drug effects
  • HIV Long Terminal Repeat
  • HIV-1 / drug effects*
  • HIV-1 / physiology*
  • Humans
  • Immunophenotyping
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Mice
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology
  • Transcription, Genetic
  • Virus Activation / drug effects*
  • Virus Latency / drug effects*

Substances

  • BANF1 protein, human
  • Biomarkers
  • DNA-Binding Proteins
  • Nuclear Proteins