title: Selective histonedeacetylase inhibitor M344 intervenes in HIV-1 latency through increasing histone acetylation and activation of NF-kappaB.
abstract: BACKGROUND
  Histone deacetylase (HDAC) inhibitors present an exciting new approach to activate HIV production from latently infected cells to potentially enhance elimination of these cells and achieve a cure. M344, a novel HDAC inhibitor, shows robust activity in a variety of cancer cells and relatively low toxicity compared to trichostatin A (TSA). However, little is known about the effects and action mechanism of M344 in inducing HIV expression in latently infected cells.
  
  
  RESULTS
  Using the Jurkat T cell model of HIV latency, we demonstrate that M344 effectively reactivates HIV-1 gene expression in latently infected cells. Moreover, M344-mediated activation of the latent HIV LTR can be strongly inhibited by a NF-κB inhibitor aspirin. We further show that M344 acts by increasing the acetylation of histone H3 and histone H4 at the nucleosome 1 (nuc-1) site of the HIV-1 long terminal repeat (LTR) and by inducing NF-κB p65 nuclear translocation and direct RelA DNA binding at the nuc-1 region of the HIV-1 LTR. We also found that M344 synergized with prostratin to activate the HIV-1 LTR promoter in latently infected cells.
  
  
  CONCLUSIONS
  These results suggest the potential of M344 in anti-latency therapies and an important role for histone modifications and NF-κB transcription factors in regulating HIV-1 LTR gene expression.
authors.affiliation: State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ying
authors.forename: Yuhao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Xiying
authors.initials: X
authors.lastname: Qu
authors.forename: Pengfei
authors.initials: P
authors.lastname: Wang
authors.forename: Sijie
authors.initials: S
authors.lastname: Liu
authors.forename: Daru
authors.initials: D
authors.lastname: Lu
authors.forename: Huanzhang
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004357:Drug Synergism; D005434:Flow Cytometry; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D016325:HIV Long Terminal Repeat / Q000187:drug effects / Q000235:genetics; D015497:HIV-1; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007150:Immunohistochemistry; D019169:Jurkat Cells; D008856:Microscopy, Fluorescence; D016328:NF-kappa B / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D011419:Propidium; D017735:Virus Latency / Q000187:drug effects*; D000077337:Vorinostat
chemical_list: D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D016328:NF-kappa B; D010703:Phorbol Esters; D049452:Green Fluorescent Proteins; D011419:Propidium; C012589:trichostatin A; D000077337:Vorinostat; C070999:prostratin