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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 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.