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Journal of Virology, November 2005, p. 14069-14078, Vol. 79, No. 22
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.22.14069-14078.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Induction of Cell Cycle Arrest by Human T-Cell Lymphotropic Virus Type 1 Tax in Hematopoietic Progenitor (CD34⁺) Cells: Modulation of p21^cip1/waf1 and p27^kip1 Expression

Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, New York,¹ Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84312,² Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263³

Received 8 March 2005/ Accepted 23 August 2005

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia, an aggressive CD4⁺ malignancy. Although HTLV-2 is highly homologous to HTLV-1, infection with HTLV-2 has not been associated with lymphoproliferative disorders. Lentivirus-mediated transduction of CD34⁺ cells with HTLV-1 Tax (Tax1) induced G₀/G₁ cell cycle arrest and resulted in the concomitant suppression of multilineage hematopoiesis in vitro. Tax1 induced transcriptional upregulation of the cdk inhibitors p21^cip1/waf1 (p21) and p27^kip1 (p27), and marked suppression of hematopoiesis in immature (CD34⁺/CD38^–) hematopoietic progenitor cells in comparison to CD34⁺/CD38⁺ cells. HTLV-1 infection of CD34⁺ cells also induced p21 and p27 expression. Tax1 also protected CD34⁺ cells from serum withdrawal-mediated apoptosis. In contrast, HTLV-2 Tax (Tax2) did not detectably alter p21 or p27 gene expression, failed to induce cell cycle arrest, failed to suppress hematopoiesis in CD34⁺ cells, and did not protect cells from programmed cell death. A Tax2/Tax1 chimera encoding the C-terminal 53 amino acids of Tax1 fused to Tax2 (Tax²²¹) displayed a phenotype in CD34⁺ cells similar to that of Tax1, suggesting that unique domains encoded within the C terminus of Tax1 may account for the phenotypes displayed in human hematopoietic progenitor cells. These remarkable differences in the activities of Tax1 and Tax2 in CD34⁺ hematopoietic progenitor cells may underlie the sharp differences observed in the pathogenesis resulting from infection with HTLV-1 and HTLV-2.

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