title: Histonedeacetylase inhibitor Oxamflatin increase HIV-1 transcription by inducing histone modification in latently infected cells.
abstract: HIV-1 latency represents a major problem in the eradication of HIV-1 in infected individuals treated with highly active anti-retroviral therapy. Histone deacetylase (HDAC) inhibits HIV-1 gene expression and virus production and may contribute to quiescence of HIV-1 within resting CD4+ T cells. Here, we evaluated the effect of Oxamflatin, a class I HDAC inhibitor, on the epigenetic change at HIV-1 long terminal repeat (LTR) and the induction of the latent viruses in the latency Jurkat T cell line. Flow cytometry assay showed that Oxamflatin activate HIV-1 gene expression in these latently infected cells by 2-17 fold than background levels. Chromatin immunoprecipitation (ChIP) assays further revealed that Oxamflatin increase the acetylation level of histone H3 and histone H4 at the nucleosome 1(nuc-1) site of the HIV-1 LTR compared to mock treatment. We also found that Oxamflatin had a synergization with prostratin, or 5-azacytidine or tumor necrosis factor-α to activate the HIV-1 promoter. Taken together, our results suggest that the histone acetylation plays an important role in regulating HIV-1 LTR gene expression, and Oxamflatin has potential as drug candidates as antilatency therapies.
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai 200433, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Huanzhang
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D019169:Jurkat Cells; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects / Q000235:genetics
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C100692:oxamflatin; C012589:trichostatin A