Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive malignant proliferation of activated CD4+ T lymphocytes. The viral Tax oncoprotein is critically involved in both HTLV-1-replication and T-cell proliferation, a prerequisite to the development of ATLL. In this study, we investigated the in vivo contribution of the Tax PDZ domain-binding motif (PBM) to the lymphoproliferative process. To that aim, we examined T-cell proliferation in humanized mice (hu-mice) carrying a human hemato-lymphoid system infected with either a wild type (WT) or a Tax PBM-deleted (ΔPBM) provirus. We observed that the frequency of CD4+ activated T-cells in the peripheral blood and in the spleen was significantly higher in WT than in ΔPBM hu-mice. Likewise, human T-cells collected from WT hu-mice and cultivated in vitro in presence of interleukin-2 were proliferating at a higher level than those from ΔPBM animals. We next examined the association of Tax with the Scribble PDZ protein, a prominent regulator of T-cell polarity, in human T-cells analyzed either after ex vivo isolation or after in vitro culture. We confirmed the interaction of Tax with Scribble only in T-cells from the WT hu-mice. This association correlated with the presence of both proteins in aggregates at the leading edge of the cells and with the formation of long actin filopods. Finally, data from a comparative genome-wide transcriptomic analysis suggested that the PBM-PDZ association is implicated in the expression of genes regulating proliferation, apoptosis and cytoskeletal organization. Collectively, our findings suggest that the Tax PBM is an auxiliary motif that contributes to the sustained growth of HTLV-1 infected T-cells in vivo and in vitro and is essential to T-cell immortalization.

Highlights

  • Human T-cell leukemia virus type 1 (HTLV-1) (Human T-cell leukemia virus, type 1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive and fatal form of leukemia characterized by the malignant expansion of activated CD4+ T-cells [1]

  • We compare the in vivo involvement of the Tax PDZ domainBinding Motif (PBM) in humanized mice infected with either a full-length provirus or a Tax PBM-deleted provirus

  • We observe that the establishment of the sustained lymphoproliferation in the peripheral blood of infected mice is dependent on the Tax PBM

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Summary

Introduction

HTLV-1 (Human T-cell leukemia virus, type 1) is the etiological agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive and fatal form of leukemia characterized by the malignant expansion of activated CD4+ T-cells [1]. Like other viral oncoproteins such as human adenovirus E4-ORF1 and human papillomavirus (HPV) E6, Tax encodes a carboxyl-terminal (ETEV amino acids 350–353) PDZ domainBinding Motif (PBM) that mediates interactions with a particular group of cellular proteins containing one or several PDZ (PSD95/DLG/ZO-1) domain(s) [7,8,9]. Many of these PDZ proteins are involved in processes that control cell attachment, cell proliferation, cell polarity and cell signaling [10, 11]. Scribble that acts as a tumor suppressor and a regulator of cell polarity, is highly expressed in activated T-lymphocytes [17, 18]

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