HTLV-I AND ASTROCYTES: IMPLICATION OF THE VIRAL PROTEIN TAX-1 AND TNFA IN THE MODULATION OF GLUTAMATE UPTAKE AND CATABOLISM.

Abstract

P041 HTLV-I is the causative agent of a chronic progressive myelopathy (HAM/TSP). In this disease, lesions of the central nervous system (CNS) are associated with perivascular and lymphocytic infiltration. We and others have hypothesized that T-lymphocytes infiltrating the CNS may play a critical role in HAM/TSP. Here, we show that a transient contact of rat or human astrocytes in primary culture with T lymphocytes chronically infected by HTLV-I is sufficient to infect these astrocytes and impair some of their major metabolic functions. Thus, the uptake of extracellular glutamate, which is primarily astrocytic in brain, was decreased by more than 50% in the late stage of infection. The expression of glial transporter GLT-1 was concomittantly decreased. The expression of astrocytic enzymes catabolizing glutamate was increased for glutamine synthetase (GS) and decreased for glutamate dehydrogenase (GDH). We have previously shown that the viral protein Tax-1 may transactivate GS promoter to induce the over-expression of the enzyme. Such hypothesis was further substantiated by the positive correlation herein observed between the mRNAs content encoding Tax-1 and the changes in GS and GDH expression. It should be stressed that even non-infectious HTLV-I T-lymphocytes produced similar alterations, presumably via secreted cytokines and Tax-1. We observed that TNFa was able to decrease glutamate uptake in astrocytes in a dose-dependent fashion. As Tax-1 stimulates the secretion of TNFa by astrocytes, HTLV-I infection and subsequently secreted cytokines may affect astrocytes to favor metabolic pathways leading to accumulation of extracellular glutamate, which in turn, may impair neuronal or oligodendrocytic function and survival. This work was supported by INSERM, ANRS and Sidaction.