TY - JOUR
T1 - HIV-1 Tat induces neuronal death via tumor necrosis factor-α and activation of non-N-methyl-D-aspartate receptors by a NFκB-independent mechanism
AU - New, Deborah R.
AU - Maggirwar, Sanjay B.
AU - Epstein, Leon G.
AU - Dewhurst, Stephen
AU - Gelbard, Harris A.
PY - 1998/7/10
Y1 - 1998/7/10
N2 - 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 Tat(1-86) 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 α, 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 NFκB. These findings further define cellular pathways activated by Tat, that dysregulate production of tumor necrosis factor α, and lead to activation of glutamate receptors and neuronal death during HIV-1 infection of the central nervous system.
AB - 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 Tat(1-86) 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 α, 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 NFκB. These findings further define cellular pathways activated by Tat, that dysregulate production of tumor necrosis factor α, and lead to activation of glutamate receptors and neuronal death during HIV-1 infection of the central nervous system.
UR - http://www.scopus.com/inward/record.url?scp=0032504151&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032504151&partnerID=8YFLogxK
U2 - 10.1074/jbc.273.28.17852
DO - 10.1074/jbc.273.28.17852
M3 - Article
C2 - 9651389
AN - SCOPUS:0032504151
VL - 273
SP - 17852
EP - 17858
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 28
ER -