Small Molecule Targeting of Specific BAF (mSWI/SNF) Complexes for HIV Latency Reversal

Cell Chem Biol. 2018 Dec 20;25(12):1443-1455.e14. doi: 10.1016/j.chembiol.2018.08.004. Epub 2018 Sep 6.


The persistence of a pool of latently HIV-1-infected cells despite combination anti-retroviral therapy treatment is the major roadblock for a cure. The BAF (mammalian SWI/SNF) chromatin remodeling complex is involved in establishing and maintaining viral latency, making it an attractive drug target for HIV-1 latency reversal. Here we report a high-throughput screen for inhibitors of BAF-mediated transcription in cells and the subsequent identification of a 12-membered macrolactam. This compound binds ARID1A-specific BAF complexes, prevents nucleosomal positioning, and relieves transcriptional repression of HIV-1. Through this mechanism, these compounds are able to reverse HIV-1 latency in an in vitro T cell line, an ex vivo primary cell model of HIV-1 latency, and in patient CD4+ T cells without toxicity or T cell activation. These macrolactams represent a class of latency reversal agents with unique mechanism of action, and can be combined with other latency reversal agents to improve reservoir targeting.

Keywords: ARID1A; BAF complex; HIV-1 latency; SWI/SNF; chromatin remodeling inhibitor; high-throughput screening.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Chromosomal Proteins, Non-Histone / antagonists & inhibitors*
  • Chromosomal Proteins, Non-Histone / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / growth & development
  • High-Throughput Screening Assays
  • Mice
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Transcription, Genetic / drug effects*
  • Virus Latency / drug effects*
  • Virus Latency / genetics


  • Chromosomal Proteins, Non-Histone
  • SWI-SNF-B chromatin-remodeling complex
  • Small Molecule Libraries
  • Transcription Factors