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Journal of Virology, February 2007, p. 1690-1700, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.01513-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Proinflammatory Cytokine Gene Induction by Human T-Cell Leukemia Virus Type 1 (HTLV-1) and HTLV-2 Tax in Primary Human Glial Cells{triangledown}

Prabal Banerjee,1 Rosemary Rochford,1 J. Antel,3 G. Canute,2 Stephen Wrzesinski,1 Michelle Sieburg,1 and Gerold Feuer1*

Department of Microbiology and Immunology,1 Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, New York 13210,2 Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada3

Received 14 July 2006/ Accepted 14 November 2006

Infection with human T-cell leukemia virus type 1 (HTLV-1) can result in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic inflammatory disease of the central nervous system (CNS). HTLV-2 is highly related to HTLV-1 at the genetic level and shares a high degree of sequence homology, but infection with HTLV-2 is relatively nonpathogenic compared to HTLV-1. Although the pathogenesis of HAM/TSP remains to be fully elucidated, previous evidence suggests that elevated levels of the proinflammatory cytokines in the CNS are associated with neuropathogenesis. We demonstrate that HTLV-1 infection in astrogliomas results in a robust induction of interleukin-1ß (IL-1ß), IL-1{alpha}, tumor necrosis factor alpha (TNF-{alpha}), TNF-ß, and IL-6 expression. HTLV encodes for a viral transcriptional transactivator protein named Tax that also induces the transcription of cellular genes. To investigate and compare the effects of Tax1 and Tax2 expression on the dysregulation of proinflammatory cytokines, lentivirus vectors were used to transduce primary human astrocytomas and oligodendrogliomas. The expression of Tax1 in primary human astrocytomas and oligodendrogliomas resulted in significantly higher levels of proinflammatory cytokine gene expression compared to Tax2. Notably, Tax1 expression uniquely sensitized primary human astrocytomas to apoptosis. A Tax2/Tax1 chimera encoding the C-terminal 53 amino acids of the Tax1 fused to the Tax2 gene (Tax221) demonstrated a phenotype that resembled Tax1, with respect to proinflammatory cytokine gene expression and sensitization to apoptosis. The patterns of differential cytokine induction and sensitization to apoptosis displayed by Tax1 and Tax2 may reflect differences relating to the heightened neuropathogenicity associated with HTLV-1 infection and the development of HAM/TSP.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210. Phone: (315) 464-7671. Fax: (315) 464-7682. E-mail: feuerg{at}upstate.edu.

{triangledown} Published ahead of print on 22 November 2006.

Journal of Virology, February 2007, p. 1690-1700, Vol. 81, No. 4
0022-538X/07/$08.00+0     doi:10.1128/JVI.01513-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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