Human immunodeficiency virus type 1 tat activates non-N-methyl-D-aspartate excitatory amino acid receptors and causes neurotoxicity.
The human immunodeficiency virus type 1 (HIV-1) protein Tat is known to be released from HIV-1-infected cells. We show that micromolar concentrations of Tat depolarized young rat and adult human neurons. In addition, Tat, at similar concentrations, was toxic to human fetal neurons in culture. Tat-induced responses were insensitive to the Na+ channel blocker tetrodotoxin, suggesting a direct effect of Tat on neurons. Tat-induced depolarizations and cytotoxicity were blocked by the excitatory amino acid antagonist kynurenate. The N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonovalerate had little effect on Tat-induced depolarizations but did provide protection from Tat neurotoxicity. These results suggest that Tat, released from HIV-1-infected cells, may be an important mediator of neurotoxicity observed in HIV-1 encephalopathy.
Magnuson
D S
DS
Department of Physiology, University of Manitoba, Winnipeg, Canada.
Knudsen
B E
BE
Geiger
J D
JD
Brownstone
R M
RM
Nath
A
A
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D015526:AIDS Dementia Complex / Q000209:etiology*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005333:Fetus; D015696:Gene Products, tat / Q000502:physiology*; D015497:HIV-1; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007736:Kynurenic Acid / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017459:Receptors, Amino Acid / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D017459:Receptors, Amino Acid; D054322:tat Gene Products, Human Immunodeficiency Virus; D013779:Tetrodotoxin; D015763:2-Amino-5-phosphonovalerate; D007736:Kynurenic Acid