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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 p21cip1/waf1 and p27kip1 Expression

Adam Tripp,1 Prabal Banerjee,1 Michelle Sieburg,1 Vicente Planelles,2 Fengzhi Li,3 and Gerold Feuer1*

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 p21cip1/waf1 (p21) and p27kip1 (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.

* Corresponding author. Mailing address: Department of Microbiology & Immunology, SUNY Upstate Medical University, 750 East Adams St., Syracuse, NY 13210. Phone: 315-464-7681. Fax: 315-464-7682. E-mail: feuerg{at}upstate.edu.

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.



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