Grant Christian, Jain Pooja, Nonnemacher Michael, Flaig Katherine E, Irish Bryan, Ahuja Jaya, Alexaki Aikaterini, Alefantis Timothy, Wigdahl Brian
Viral Immunology Section, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
J Leukoc Biol. 2006 Sep;80(3):640-50. doi: 10.1189/jlb.1205723. Epub 2006 Jul 7.
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.
先前已证明，人类1型T细胞白血病病毒（HTLV-1）可在体内感染抗原呈递细胞及其前体。然而，这些重要细胞群体在HTLV-1相关脊髓病/热带痉挛性截瘫或成人T细胞白血病发病机制中所起的作用仍未明确。为了更好地理解HTLV-1感染这些重要细胞群体可能如何影响疾病进展，研究了已建立的单核细胞系中HTLV-1病毒基因表达的调控情况。用佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）处理瞬时转染了HTLV-1长末端重复序列（LTR）荧光素酶构建体的U-937原单核细胞，以诱导细胞分化。PMA诱导的细胞分化导致HTLV-1 LTR的基础激活和Tax介导的反式激活。此外，电泳迁移率变动分析表明，PMA诱导的细胞分化诱导了细胞转录因子与Tax反应元件1（TRE-1）重复序列II的DNA结合活性。超迁移分析显示，在细胞分化过程中，属于碱性区域/亮氨酸拉链蛋白激活蛋白1（AP-1）家族的因子（Fra-1、Fra-2、JunB和JunD）被诱导与TRE-1重复序列II结合。在瞬时表达分析中，通过过表达显性负性c-Fos突变体（A-Fos）抑制AP-1 DNA结合活性，导致PMA诱导的U-937细胞中HTLV-1 LTR激活水平严重降低。这些结果表明，外周血单核细胞感染HTLV-1后，在分化为巨噬细胞或树突状细胞的过程中，AP-1可能会上调HTLV-1病毒基因表达。
