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Journal of Virology, July 2000, p. 6433-6441, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Human T-Cell Lymphotropic Virus Type 1-Infected T Lymphocytes Impair Catabolism and Uptake of Glutamate by Astrocytes via Tax-1 and Tumor Necrosis Factor Alpha

Raphaël Szymocha,1 Hideo Akaoka,1 Magali Dutuit,1 Christophe Malcus,2 Marianne Didier-Bazes,1 Marie-Françoise Belin,1 and Pascale Giraudon1,*

Experimental Neurobiology and Physiopathology Unit, INSERM U433,1 and Hôpital Neurologique,2 Lyon, France

Received 3 December 1999/Accepted 26 April 2000

Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of a chronic progressive myelopathy called tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). In this disease, lesions of the central nervous system (CNS) are associated with perivascular infiltration by lymphocytes. We and others have hypothesized that these T lymphocytes infiltrating the CNS may play a prominent role in TSP/HAM. Here, we show that transient contact of human or rat astrocytes with T lymphocytes chronically infected by HTLV-1 impairs some of the major functions of brain astrocytes. Uptake of extracellular glutamate by astrocytes was significantly decreased after transient contact with infected T cells, while the expression of the glial transporters GLAST and GLT-1 was decreased. In two-compartment cultures avoiding direct cell-to-cell contact, similar results were obtained, suggesting possible involvement of soluble factors, such as cytokines and the viral protein Tax-1. Recombinant Tax-1 and tumor necrosis factor alpha (TNF-alpha ) decreased glutamate uptake by astrocytes. Tax-1 probably acts by inducing TNF-alpha , as the effect of Tax-1 was abolished by anti-TNF-alpha antibody. The expression of glutamate-catabolizing enzymes in astrocytes was increased for glutamine synthetase and decreased for glutamate dehydrogenase, the magnitudes of these effects being correlated with the level of Tax-1 transcripts. In conclusion, Tax-1 and cytokines produced by HTLV-1-infected T cells impair the ability of astrocytes to manage the steady-state level of glutamate, which in turn may affect neuronal and oligodendrocytic functions and survival.

* Corresponding author. Mailing address: INSERM U433, Faculté de Médecine Laënnec, F69372 Lyon cedex 08, France. Phone: (33) 4 7877 8759. Fax: (33) 4 7877 8616. E-mail: giraudon{at}lyon151.inserm.fr.

Journal of Virology, July 2000, p. 6433-6441, Vol. 74, No. 14
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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