TUMOR-NECROSIS-FACTOR-ALPHA INHIBITS GLUTAMATE UPTAKE BY PRIMARY HUMAN ASTROCYTES - IMPLICATIONS FOR PATHOGENESIS OF HIV-1 DEMENTIA

Human immunodeficiency virus (HIV) infection is commonly associated wi th neurological disease that occurs in the apparent absence of extensi ve infection of brain cells by HIV, suggesting that indirect mechanism s account for neuropathogenesis in the CNS, perhaps including changes in the normal neuroprotective functions of astrocytes. To test this hy pothesis, we examined the effect of the pro-inflammatory cytokine, tum or necrosis factor alpha (TNF alpha), produced by HIV-1-infected macro phages and microglia, on glutamate transport by primary human fetal as trocytes (PHFAs). A dose-dependent inhibition of high affinity glutama te uptake sites was observed 12-24 h after addition of exogenous recom binant human TNF alpha to PHFAs. This effect was specific since it was blocked by a neutralizing monoclonal antibody directed against TNF al pha. Furthermore, the inhibitory effect was reproduced by a monoclonal antibody that is an agonist at the 55-kDa TNF receptor. These results suggest that the neurotoxic effects of TNF alpha may be due in part t o its ability to inhibit glutamate uptake by astrocytes, which in turn may result in excitotoxic concentrations of glutamate in synapses.