AP-1-directed human T cell leukemia virus type 1 viral gene expression during monocytic differentiation

Human T cell leukemia virus type 1 (HTLV-1) has previously been shown to infect anti- gen-presenting cells and their precursors in vivo. However, the role these important cell populations play in the pathogenesis of HTLV-1-associated my- elopathy/tropical spastic paraparesis or adult T cell leukemia remains unresolved. To better understand how HTLV-1 infection of these important cell popu- lations 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 acti- vation of basal and Tax-mediated transactivation of the HTLV-1 LTR. In addition, electrophoretic mo- bility 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 re- vealed that factors belonging to the activator protein 1 (AP-1) family of basic region/leucine zipper pro- teins (Fra-1, Fra-2, JunB, and JunD) were induced to bind to TRE-1 repeat II during cellular differentia- tion. 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 sug- gested that following infection of peripheral blood monocytes, HTLV-1 viral gene expression may be- come up-regulated by AP-1 during differentiation into macrophages or dendritic cells. J. Leukoc. Biol. 80: 640-650; 2006.