HIV-1 Tat induces neuronal death via tumor necrosis factor-alpha and activation of non-N-methyl-D-aspartate receptors by a NFkappaB-independent mechanism.

Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system may result in neuronal apoptosis in vulnerable brain regions, including cerebral cortex and basal ganglia. The mechanisms for neuronal loss are likely to be multifactorial and indirect, since HIV-1 productively infects brain-resident macrophages and microglia but does not cause cytolytic infection of neurons in the central nervous system. HIV-1 infection of macrophages and microglia leads to production and release of diffusible factors that result in neuronal cell death, including the HIV-1 regulatory protein Tat. We demonstrate in this report that recombinant Tat1-86 and Tat peptides containing the basic region induce neuronal apoptosis in approximately 50% of vulnerable neurons in both rat and human neuronal cultures, and this apoptotic cell death is mediated by release of the pro-inflammatory cytokine tumor necrosis factor alpha, and by activation of glutamate receptors of the non-N-methyl-D-aspartate subtype. Finally, we show that Tat-induced apoptosis of human neuronal cell cultures occurs in the absence of activation of the transcription factor NFkappaB. These findings further define cellular pathways activated by Tat, that dysregulate production of tumor necrosis factor alpha, and lead to activation of glutamate receptors and neuronal death during HIV-1 infection of the central nervous system.

Human immunodeficiency virus type 1 Tat protein induces death by apoptosis in primary human neuron cultures.

Neuronal loss in HIV encephalopathy remains a mystery since HIV-1 productively infects macrophage and microglia and only rarely infects neurons in the central nervous system. Apoptosis is a mechanism which may account for the loss of neurons in HIV-1 infected brain. Putative toxic factors that result in neuronal cell death in HIV-1 infection include the regulatory protein Tat, since this protein is known to be released from HIV-1 infected cells. Here we show that Tat induces cell death by apoptosis in cultured human fetal neurons producing characteristic morphological and biochemical features associated with apoptosis. These findings suggest that Tat may play an important role as a secreted, soluble neurotoxin in HIV-1 associated dementia.