Neuronal excitatory properties of human immunodeficiency virus type 1 Tat protein

• Published in: Neuroscience Vol. 82; no. 1; pp. 97 - 106
• Main Authors: CHENG, J, NATH, A, KNUDSEN, B, HOCHMAN, S, GEIGER, J. D, MA, M, MAGNUSON, D. S. K
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 1998
• Subjects: Animals; Biological and medical sciences; Calcium - physiology; Electric Stimulation; Electrophysiology; Fundamental and applied biological sciences. Psychology; Gene Products, tat - pharmacology; Hippocampus - cytology; Hippocampus - physiology; HIV-1 - metabolism; Humans; Membrane Potentials - drug effects; Membrane Potentials - physiology; Microbiology; Neurons - drug effects; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Replicative cycle, interference, host-virus relations, pathogenicity, miscellaneous strains; Stimulation, Chemical; tat Gene Products, Human Immunodeficiency Virus; Tetrodotoxin - pharmacology; Virology; Human; Calcium; HIV-1 virus; Electrophysiology; Retroviridae; Patch clamp method; Lentivirus; In vitro; Virus; Depolarization; Infection; Neuron; Human immunodeficiency virus
• ISSN: 0306-4522; 1873-7544

Neuronal dysfunction and cell death in patients with human immunodeficiency virus type-1 (HIV-1) infection may be mediated by HIV-1 proteins and products released from infected cells. Two HIV-1 proteins, the envelope glycoprotein gp120 and nonstructural protein Tat, are neurotoxic. We have determined the neuroexcitatory properties of HIV-1 tat protein using patch-clamp recording techniques. When fmoles of Tat were applied extracellularly, it elicited dose-dependent depolarizations of human fetal neurons in culture and rat CA1 neurons in slices, both in the absence and presence of tetrodotoxin. These responses were voltage-dependent, reversed at approximately 0 mV, and were significantly increased by repetitive applications with no evidence of desensitization. That these responses to Tat were due to direct actions on neurons was supported by observations that Tat dose-dependently depolarized outside-out patches excised from cultured human neurons. Removal of extracellular Ca2+ decreased the responses both in neurons and membrane patches. This is the first demonstration that an HIV-1 protein can, in the absence of accessory cells, directly excite neurons and leads us to speculate that Tat may be a causative agent in HIV-1 neurotoxicity.