Immortalization of CD4+ and CD8+ T Lymphocytes by Human T-Cell Leukemia Virus Type 1 Tax Mutants Expressed in a Functional Molecular Clone

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Journal of Virology, June 1999, p. 4856-4865, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Immortalization of CD4⁺ and CD8⁺ T Lymphocytes by Human T-Cell Leukemia Virus Type 1 Tax Mutants Expressed in a Functional Molecular Clone

Michael D. Robek and Lee Ratner^*

Departments of Medicine, Pathology, and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110

Received 25 November 1998/Accepted 8 March 1999

The human T-cell leukemia virus type 1 (HTLV-1) transcriptional trans-activator Tax has been demonstrated to have transformingactivity in multiple cell culture and transgenic-mouse models.In addition to activating transcription from the viral long terminalrepeat (LTR) through the cyclic AMP response element binding protein/activatingtranscription factor (CREB/ATF) family of transcription factors,Tax activates the expression of multiple cellular promoters throughthe NF- $kappa$ B pathway of transcriptional activation. The Tax mutantsM22 and M47 have previously been demonstrated to selectively abrogatethe ability of Tax to activate transcription through the NF- $kappa$ Bor CREB/ATF pathway, respectively. These mutations were introducedin the tax gene of the ACH functional molecular clone of HTLV-1,and virus produced from the mutant ACH clones was examined forthe ability to replicate and immortalize primary human lymphocytes.While virus derived from the clone containing the M47 mutationretained the ability to immortalize T lymphocytes, the M22 mutantlost the ability to immortalize infected cells. These resultsindicate that activation of the CREB/ATF pathway by Tax is dispensablefor the immortalization of T cells by HTLV-1, whereas activationof the NF- $kappa$ B pathway may becritical.

^* Corresponding author. Mailing address: Division of Molecular Oncology, Department of Medicine, Box 8069, 660 South EuclidAve., St. Louis, MO 63110. Phone: (314) 362-8836. Fax: (314) 747-2797.E-mail: lratner{at}imgate.wustl.edu.

Journal of Virology, June 1999, p. 4856-4865, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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