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Yujie Liu,
Michael R Nonnemacher,
Devin L Stauff,
Luna Li,
Anupam Banerjee, Bryan Irish,
Evelyn Kilareski,
Nirmala Rajagopalan,
Joyce B Suchitra,
Zafar K Khan,
Udaykumar Ranga,
Brian Wigdahl
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ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) subtype C, which is most predominant in sub-Saharan Africa as well as in Asia and India, is the most prevalent subtype worldwide. A large number of transcription factor families have been shown to be involved in regulating HIV-1 gene expression in T lymphocytes and cells of the monocyte-macrophage lineage. Among these, proteins of the CCAAT/enhancer binding protein (C/EBP) family are of particular importance in regulating HIV-1 gene expression within cells of the monocytic lineage during the course of hematologic development and cellular activation. Few studies have examined the role of C/EBPs in long terminal repeat (LTR)-directed viral gene expression of HIV-1 subtypes other than subtype B. Within subtype B viruses, two functional C/EBP sites located upstream of the TATA box are required for efficient viral replication in cells of the monocyte-macrophage lineage. We report the identification of three putative subtype C C/EBP sites, upstream site 1 and 2 (C-US1 and C-US2) and downstream site 1 (C-DS1). C-US1 and C-DS1 were shown to form specific DNA-protein complexes with members of the C/EBP family (C/EBPα, β, and δ). Functionally, within the U-937 monocytic cell line, subtype B and C LTRs were shown to be equally responsive to C/EBPβ-2, although the basal activity of subtype C LTRs appeared to be higher. Furthermore, the synergistic interaction between C/EBPβ-2 and Tat with the subtype C LTR was also observed in U-937 cells as previously demonstrated with the subtype B LTR.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 09/2010; 64(10):672-80. · 2.24 Impact Factor
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ABSTRACT: Cells of the monocyte-macrophage lineage play an important role in human immunodeficiency virus type 1 (HIV-1)-associated disease. Infected myeloid precursor cells of the bone marrow are thought to be a viral reservoir that may repopulate the peripheral blood, central nervous system (CNS), and other organ systems throughout the course of disease. To model select aspects of HIV-1 infection of the bone marrow compartment in vitro, the erythro-myeloid precursor cell line, TF-1, was used. Phorbol 12-myristate 13-acetate (PMA) was found to induce the TF-1 cell line to differentiate through the myeloid lineage and become activated, as demonstrated by cellular morphologic changes and surface expression of differentiation and activation markers. Herein we demonstrate that HIV-1 long terminal repeats (LTRs) from T-, M-, and dual-tropic molecular clones have similar basal LTR activity in TF-1 cells and that differentiation of these cells by PMA resulted in increased LTR activity. Examination of specific cis-acting elements involved in basal and PMA-induced LTR activity demonstrated that the transcription factor families nuclear factor-kappa B (NF-kappaB) and specificity protein (Sp) contributed to the LTR activity of TF-1 cells, the Sp family being the most critical. These studies elucidate the impact of infected bone marrow monocytic cell differentiation on LTR activity and its potential impact on HIV-1-associated disease.
DNA and Cell Biology 07/2007; 26(6):387-94. · 2.07 Impact Factor
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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.
Journal of Leukocyte Biology 10/2006; 80(3):640-50. · 4.99 Impact Factor
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ABSTRACT: CCAAT/enhancer-binding protein (C/EBP) basic region/leucine zipper (bZIP) transcription factors have been shown to form heterodimers with cAMP-responsive element binding protein 2 (CREB-2), a transcription factor involved in regulating basal and Tax-mediated transactivation of the human T cell leukemia virus type 1 (HTLV-1) long terminal repeat (LTR). In cells of the monocyte-macrophage lineage (proposed to play a role in HTLV-1 pathogenesis as an accessory target cell), several members of the C/EBP family are expressed at high levels and may have functional impact on both basal and Tax-mediated transactivation of the HTLV-1 LTR. Basal activation of the HTLV-1 LTR was enhanced by overexpression of C/EBPbeta, C/EBPdelta, or C/EBPepsilon, whereas transactivation of the LTR by Tax was inhibited by overexpression of C/EBPalpha and C/EBPbeta. Inhibition of Tax-mediated transactivation of the HTLV-1 LTR was co-activator-independent, did not require C/EBP binding to the Tax-responsive elements, and may involve heterodimerization with CREB factors.
Virology 06/2006; 348(2):354-69. · 3.35 Impact Factor
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Retrovirology. 01/2005;
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Retrovirology. 01/2005;
