title: Hexamethylbisacetamide remodels the human immunodeficiency virus type 1 (HIV-1) promoter and induces Tat-independent HIV-1 expression but blunts cell activation.
abstract: Hexamethylbisacetamide (HMBA) induces human immunodeficiency virus type 1 (HIV-1) gene expression in latently infected T-cell and monocytoid cell lines. We find that HMBA activation of viral expression is Tat independent but, like Tat, increases the efficiency of elongation of the HIV-1 promoter (long terminal repeat [LTR]) transcripts. Further, exposure to HMBA induces chromatin remodeling at nucleosome 1 (Nuc-1) near the start site of LTR transcription but does so without increasing histone acetylation or altering histone methylation near Nuc-1. Of note, despite enhanced proviral expression, HMBA suppressed HIV infection ex vivo in primary blood mononuclear cell (PBMC) cultures. Treatment with HMBA did not alter expression of the HIV coreceptors, CCR5 and CXCR4, in PBMCs but down-regulated CD4. Finally, HMBA interferes with cell proliferation and activation; it suppressed expression of Ki67 and CD25 and in PBMCs exposed to mitogen. As HMBA has been tested in oncology trials, its unusual properties make it a useful reagent for future studies of HIV promoter regulation and a novel prototype molecule for therapeutics that abort the latent proviral state of chronic HIV infection.
authors.affiliation: North Texas Veterans Health Care Systems, Dallas, Texas 75216, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Klichko
authors.forename: Nancy
authors.initials: N
authors.lastname: Archin
authors.forename: Rupinderjeet
authors.initials: R
authors.lastname: Kaur
authors.forename: Ginger
authors.initials: G
authors.lastname: Lehrman
authors.forename: David
authors.initials: D
authors.lastname: Margolis
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D015415:Biomarkers; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D004706:Endodeoxyribonucleases / Q000378:metabolism; D015967:Gene Expression Regulation, Viral / Q000187:drug effects* / Q000235:genetics; D015696:Gene Products, tat / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006657:Histones / Q000235:genetics; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D000081:Acetamides; D015415:Biomarkers; D015704:CD4 Antigens; D015696:Gene Products, tat; D006657:Histones; D019394:Ki-67 Antigen; D015375:Receptors, Interleukin-2; D011991:Receptors, Virus; D054322:tat Gene Products, Human Immunodeficiency Virus; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II