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

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 ne rvous system (CNS) are associated with perivascular infiltration by lymphoc ytes. 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 avo iding direct cell-to-cell contact, similar results were obtained, suggestin g 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 increa sed for glutamine synthetase and decreased for glutamate dehydrogenase, the magnitudes of these effects being correlated with the level of Tax-1 trans cripts. In conclusion, Tax-1 and cytokines produced by HTLV-1-infected T ce lls impair the ability of astrocytes to manage the steady-state level of gl utamate, which in turn may affect neuronal and oligodendrocytic functions a nd survival.