Synergistic neurotoxicity by human immunodeficiency virus proteins Tat and gp120: protection by memantine.
Human immunodeficiency virus type 1 (HIV-1) proteins Tat and gp120 have been implicated in the pathogenesis of dementia associated with HIV infection. Recently, we showed the presence of Tat protein in brains of patients with HIV-1 encephalitis as well as macaques with encephalitis caused by a chimeric strain of HIV and simian immunodeficiency virus, and that even transient exposure of cells to Tat leads to release of cytopathic cytokines. Now, we report the first demonstration of gp120 protein in brain of patients with HIV encephalitis. We tested the hypothesis that Tat and gp120 would act synergistically to potentiate each protein's neurotoxic effects and determined the extent to which pharmacological antagonists against processes implicated in HIV-1 neuropathogenesis could block HIV-1 protein-induced neurotoxicity. Subtoxic concentrations of Tat and gp120, when incubated together, caused neuronal cell death and prolonged increases in levels of intracellular calcium. A transient exposure of neurons to Tat and gp120 for seconds initiated neuronal cell death, but maximal levels of neuronal cell death were observed with exposures lasting 30 minutes. The neurotoxicity caused by Tat and gp120 applied in combination was blocked completely by memantine, partially by amiloride, and not at all by dipyridamole or vigabatrin.
Nath
A
A
Department of Neurology, University of Kentucky, Lexington 40536-0284, USA.
Haughey
N J
NJ
Jones
M
M
Anderson
C
C
Bell
J E
JE
Geiger
J D
JD
D015526:AIDS Dementia Complex / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000196:embryology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D004660:Encephalitis / Q000378:metabolism; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D015696:Gene Products, tat / Q000506:poisoning*; D018698:Glutamic Acid / Q000494:pharmacology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism / Q000506:poisoning*; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008559:Memantine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D013997:Time Factors; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D054322:tat Gene Products, Human Immunodeficiency Virus; D018698:Glutamic Acid; D002118:Calcium; D008559:Memantine