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J. Virol. doi:10.1128/JVI.01513-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Pro-inflammatory Cytokine Gene Induction by HTLV-1 and HTLV-2 Tax in Primary Human Glial Cells

Dept. Microbiology and Immunology, Dept of Neurosurgery, SUNY Upstate Medical University, Syracuse, NY, 13210; Dept. of Neurology and Neurosurgery, McGill University Montreal, Quebec, Canada; Department of Internal Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

^* To whom correspondence should be addressed. Email: feuerg{at}upstate.edu.

	Abstract

Infection with Human T-cell leukemia virus type1 (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 non-pathogenic in comparison to HTLV-1. Although the pathogenesis of HAM/TSP remains to be fully elucidated, previous evidence suggests that elevated levels of the pro-inflammatory cytokines in the CNS are associated with neuropathogenesis. We demonstrate that HTLV-1 infection in astrogliomas results in a robust induction of IL-1, IL-1, TNF-, TNF- and IL-6 expression. HTLV encodes for a viral transcriptional transactivator protein named Tax that also induces 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. Expression of Tax1 in primary human astrocytomas and oligodendrogliomas resulted in significantly higher levels of pro-inflammatory cytokine gene expression in comparison 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 which 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 neuro-pathogenicity associated with HTLV-1 infection and development of HAM/TSP.