Histone deacetylase inhibitor Scriptaid reactivates latent HIV-1 promoter by inducing histone modification in in vitro latency cell lines.
Human immunodeficiency virus type 1 (HIV-1) latency remains a major problem for the eradication of viruses in infected individuals undergoing highly active anti-retroviral therapy. By inhibiting HIV-1 gene expression and virus production, histone deacetylase (HDAC) may contribute to the quiescence of HIV-1 within resting CD4+ T cells. A novel HDAC inhibitor, Scriptaid, has been found to have robust activity and lower toxicity compared to trichostatin A (TSA). We therefore investigated Scriptaid for its capability to reverse HIV-1 latency by inducing HIV-1 activation in the Jurkat T cell line containing latent HIV proviruses. We found that Scriptaid can activate HIV-1 gene expression in these latent infected cells by 2-15-fold over background levels, as analyzed by flow cytometry. Chromatin immunoprecipitation (ChIP) assays further revealed that the Scriptaid increased the acetylation level of histones H3 and H4 at the nucleosome 1 site of the HIV-1 long terminal repeat compared to mock treatment. In addition, Scriptaid can synergize with prostratin or tumor necrosis factor-alpha to activate the HIV-1 promoter, with relatively lower toxicity compared to TSA. These studies suggest the potential of Scriptaid in anti-latency therapies.
Ying
Hao
H
State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, P.R. China.
Zhang
Yuhao
Y
Lin
Shiguan
S
Han
Yefei
Y
Zhu
Huan-Zhang
HZ
D000107:Acetylation / Q000187:drug effects; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D016325:HIV Long Terminal Repeat; D015497:HIV-1; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology*; D019169:Jurkat Cells; D010703:Phorbol Esters; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D011804:Quinolines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha; D017735:Virus Latency / Q000187:drug effects*
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006898:Hydroxylamines; D010703:Phorbol Esters; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; C410733:scriptaid; C070999:prostratin