IMBALANCED EXPRESSION OF GLUTAMATE-GLUTAMINE CYCLE ENZYMES INDUCED BYHUMAN T-CELL LYMPHOTROPIC VIRUS TYPE-1 TAX PROTEIN IN CULTIVATED ASTROCYTES

Human T-cell lymphotropic virus type 1 (HTLV-1) is the etiological age nt involved in the disease HTLV-1-associated myelopathy, or tropical s pastic paraparesis (HAM/TSP). The pathogenesis of HAM/TSP is poorly un derstood, but it is probable that viral infection has an indirect, del eterious effect on neural function. In this regard, dysfunction in ast rocytes may be severely detrimental, as they supply neurons with metab olic precursors, control the extracellular levels of ion and excitator y neurotransmitters, and are electrically coupled with oligodendrocyte s. In a model in vitro, we demonstrate that HTLV-1 induces an imbalanc e in the expression of two astrocyte enzymes, at both the transcriptio nal and translational levels, In both human astrocyte precursors and r at glial cells, the levels of expression of glutamine synthetase (GS) and glutamate dehydrogenase (GDH) were increased and decreased, respec tively, after coculture with HTLV-1 T cells. The enhancement of GS exp ression may result from the action of the protein Tax, which is demons trated to transactivate the GS gene promoter, while the decreased expr ession of GDH seems to reflect some compensatory mechanism in response to GS induction, GS and GDH are involved in the conversion of glutama te into glutamine or alpha-ketoglutarate, which then acts as a precurs or for glutamatergic and gamma-aminobutyric acid (GABA)-ergic neurons. Metabolism in astrocytes altered by Tax protein may lead to deleterio us effects if it modifies the extracellular levels of glutamine, gluta mate, and GABA and thus modulates neuronal excitability and osmotic eq uilibrium in the central nervous system of HTLV-1-infected patients.