Transcriptional Activation and Chromatin Remodeling of the HIV-1 Promoter in Response to Histone Acetylation

EMBO J. 1996 Mar 1;15(5):1112-20.

Abstract

After integration in the host cell genome, the HIV-1 provirus is packaged into chromatin. A specific chromatin disruption occurs in the HIV-1 promoter during transcriptional activation in response to TNF-alpha, suggesting that chromatin plays a repressive role in HIV-1 transcription and that chromatin modification(s) might result in transcriptional activation. We have treated several cell lines latently infected with HIV-1 with two new specific inhibitors of histone deacetylase, trapoxin (TPX) and trichostatin A (TSA), to cause a global hyperacetylation of cellular histones. Treatment with both drugs results in the transcriptional activation of the HIV-1 promoter and in a marked increase in virus production. Dose-response curves and kinetic analysis show a close correlation between the level of histone acetylation and HIV-1 gene expression. In contrast, both TPX and TSA have little or no effect on HIV-1 promoter activity following transient transfection of an HIV-1 promoter-reporter plasmid. Activation of HIV-1 transcription by TSA and TPX treatment occurs in the absence of NF-kappa B induction. Chromatin analysis of the HIV-1 genome shows that a single nucleosome (nuc-1) located at the transcription start and known to be disrupted following TNF-alpha treatment, is also disrupted following TPX or TSA treatment. This disruption is independent of transcription as it is resistant to alpha-amanitin. These observations further support the crucial role played by nuc-1 in the suppression of HIV-1 transcription during latency and demonstrate that transcriptional activation of HIV-1 can proceed through a chromatin modification.

Publication types

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

MeSH terms

  • Acetylation
  • Anti-Bacterial Agents / pharmacology
  • Base Sequence
  • Cell Line
  • Chromatin / genetics
  • Chromatin / metabolism
  • DNA, Viral / genetics
  • Enzyme Inhibitors / pharmacology
  • Genes, Viral* / drug effects
  • HIV-1 / genetics*
  • Histone Deacetylase Inhibitors
  • Histones / chemistry
  • Histones / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Kinetics
  • Molecular Sequence Data
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nucleosomes / metabolism
  • Peptides
  • Promoter Regions, Genetic*
  • Transcriptional Activation / drug effects
  • Transfection

Substances

  • Anti-Bacterial Agents
  • Chromatin
  • DNA, Viral
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • NF-kappa B
  • Nucleosomes
  • Peptides
  • trichostatin A