title: Hexamethylbisacetamide and disruption of human immunodeficiency virus type 1 latency in CD4(+) T cells.
abstract: BACKGROUND
  Novel therapeutic approaches are needed to attack persistent proviral human immunodeficiency type 1 (HIV-1) infection. Hexamethylbisacetamide (HMBA), a hybrid bipolar compound, induces expression of the HIV-1 promoter in the long terminal repeat (LTR) region in a Tat-independent manner but mimics the effect of Tat, overcoming barriers to LTR expression and increasing the processivity of LTR transcription complexes.
  
  
  METHODS
  We studied alterations in cellular factors and their LTR occupancy induced by HMBA in models of latent HIV-1 infection. We measured the induction of viral outgrowth by HMBA in resting CD4(+) T cells from aviremic HIV-1-infected donors.
  
  
  RESULTS
  HMBA induced outgrowth of HIV-1 from resting CD4(+) T cells recovered from aviremic patients treated with antiretroviral therapy (ART). HMBA triggered cyclin-dependent kinase 9 (CDK9) recruitment to the LTR, a key factor in the induction of efficient HIV-1 expression, via an unexpected interaction with the transcription factor Sp1. The availability of Sp1 and Sp1 DNA binding sites were necessary for HMBA-induced CDK9 recruitment and LTR expression. HMBA signaling via both protein kinase C mu and phosphatidylinositol 3-kinase appeared to contribute to LTR induction.
  
  
  CONCLUSIONS
  The novel mechanism through which HMBA disrupts latent HIV-1 infection involves 2 cellular kinases that may be therapeutically exploited to induce expression of persistent proviral HIV-1.
authors.affiliation: Departments of Medicine, University of North Carolina at Chapel Hill 27599-7435, USA.
authors.forename: Shailesh K
authors.initials: SK
authors.lastname: Choudhary
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Archin
authors.forename: David M
authors.initials: DM
authors.lastname: Margolis
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012319:RNA Polymerase II / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D000081:Acetamides; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D012367:RNA, Viral; D016329:Sp1 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; C089212:protein kinase D; D011493:Protein Kinase C; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D012319:RNA Polymerase II; C014026:hexamethylene bisacetamide