title: AP-1-directed human T cell leukemia virus type 1 viral gene expression during monocytic differentiation.
abstract: Human T cell leukemia virus type 1 (HTLV-1) has previously been shown to infect antigen-presenting cells and their precursors in vivo. However, the role these important cell populations play in the pathogenesis of HTLV-1-associated myelopathy/tropical spastic paraparesis or adult T cell leukemia remains unresolved. To better understand how HTLV-1 infection of these important cell populations may potentially impact disease progression, the regulation of HTLV-1 viral gene expression in established monocytic cell lines was examined. U-937 promonocytic cells transiently transfected with a HTLV-1 long-terminal repeat (LTR) luciferase construct were treated with phorbol 12-myristate 13-acetate (PMA) to induce cellular differentiation. PMA-induced cellular differentiation resulted in activation of basal and Tax-mediated transactivation of the HTLV-1 LTR. In addition, electrophoretic mobility shift analyses demonstrated that PMA-induced cellular differentiation induced DNA-binding activity of cellular transcription factors to Tax-responsive element 1 (TRE-1) repeat II. Supershift analyses revealed that factors belonging to the activator protein 1 (AP-1) family of basic region/leucine zipper proteins (Fra-1, Fra-2, JunB, and JunD) were induced to bind to TRE-1 repeat II during cellular differentiation. Inhibition of AP-1 DNA-binding activity by overexpression of a dominant-negative c-Fos mutant (A-Fos) in transient expression analyses resulted in severely decreased levels of HTLV-1 LTR activation in PMA-induced U-937 cells. These results have suggested that following infection of peripheral blood monocytes, HTLV-1 viral gene expression may become up-regulated by AP-1 during differentiation into macrophages or dendritic cells.
authors.affiliation: Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Grant
authors.forename: Pooja
authors.initials: P
authors.lastname: Jain
authors.forename: Michael
authors.initials: M
authors.lastname: Nonnemacher
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Flaig
authors.forename: Bryan
authors.initials: B
authors.lastname: Irish
authors.forename: Jaya
authors.initials: J
authors.lastname: Ahuja
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Alexaki
authors.forename: Timothy
authors.initials: T
authors.lastname: Alefantis
authors.forename: Brian
authors.initials: B
authors.lastname: Wigdahl
mesh_terms: D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D016356:Gene Products, tax / Q000276:immunology; D016762:Genes, fos / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D006801:Humans; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology*; D011485:Protein Binding; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D016356:Gene Products, tax; D018808:Transcription Factor AP-1; C016658:phorbolol myristate acetate; D013755:Tetradecanoylphorbol Acetate