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.

Presentation of human T cell leukemia virus type 1 (HTLV-1) Tax protein by dendritic cells: the underlying mechanism of HTLV-1-associated neuroinflammatory disease

“…3) demonstrated that DCs pulsed with the Tax 11-19 peptide induced a higher IFN-␥ response (2.15% and 8.75% CD8 ϩ /IFN-␥ ϩ T cells from mouse 1 and mouse 2, respectively) when compared with those pulsed with a HLAmismatched Gag 77-85 peptide (0.009% and 0.072% CD8 ϩ / IFN-␥ ϩ T cells from mouse 1 and mouse 2, respectively). The response obtained with the Tax [11][12][13][14][15][16][17][18][19] peptide was comparable with that obtained with the anti-CD3 antibody used as a positive control (3.81% and 7.71% CD8 ϩ /IFN-␥ ϩ T cells in mouse 1 and mouse 2, respectively). Thus, our in vivo results are comparable with those obtained with the in vitro priming studies.…”

HTLV-1 and Innate Immunity

“…Viral reactivation could then be induced upon monocyte-to-macrophage differentiation. This model is consistent with in vitro experiments showing that HTLV-1-LTR-driven luciferase transcription was activated upon differentiation of a transiently transfected monocytic cell line into macrophages, in an AP-1-dependent manner [53]. Infection of monocytes and monocyte-derived cells could be of particular interest in the context of mother-to-child transmission.…”

“…Koyanagi et al showed that the PVL ranged between 0 and 140 copies per 10 4 monocytes in a group of 22 HTLV-1-infected individuals [39]. A latent infection of monocytes, which would allow them to escape immune recognition, was hypothesized [53]. Viral reactivation could then be induced upon monocyte-to-macrophage differentiation.…”

Imaging spontaneous tumorigenesis: inflammation precedes development of peripheral NK tumors

“…In these experiments, Tax-independent basal LTR activity also increased relative to transgene copy number. Tax-independent HTLV-1 LTR activity is mediated by the Sp1, AP1, and C/EBP families of transcription factors, [21][22][23][24] can be induced by apoptosis or stress responses, [25][26][27][28] and is repressed by HDAC1 and ATFx. 29,30 However, when stably integrated in a primate cell line, the LTR-LUC transgene has low basal activity and 100-to 200-fold inducibility by retrovirally expressed Tax ( Figure 1D,E).…”