Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation.
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.
Van Lint
C
C
The Picower Institute for Medical Research, Manhasset, NY 11030, USA.
Emiliani
S
S
Ott
M
M
Verdin
E
E
D000107:Acetylation; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005814:Genes, Viral / Q000187:drug effects; D015497:HIV-1 / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007700:Kinetics; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D010455:Peptides; D011401:Promoter Regions, Genetic; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D000900:Anti-Bacterial Agents; D002843:Chromatin; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D016328:NF-kappa B; D009707:Nucleosomes; D010455:Peptides; C012589:trichostatin A