Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons.
The pathogenesis of human immunodeficiency virus type 1 (HIV-1)-associated dementia is mediated by neuronal dysfunction and death, brought about by the action of soluble neurotoxic factors that are released by virally infected macrophages and microglia. Paradoxically, many candidate HIV-1 neurotoxins also possess the ability to activate nuclear factor-kappa B (NF-kappaB), which has a potent pro-survival effect in primary neurons. The present study explored this conundrum and investigated why NF-kappaB might fail to protect neurons that are exposed to candidate HIV-1 neurotoxins. Here, we evaluated the ability of virus-depleted conditioned medium produced by HIV-1-infected human macrophages (HIV-MCMs) to modulate NF-kappaB activity in neurons. We demonstrated that HIV-MCMs inhibit the normal signaling pathways that lead to NF-kappaB activation in neurons. This inhibitory effect of HIV-MCM is dependent upon the presence of HIV-1 Tat, which activates glycogen synthase kinase (GSK)-3beta in neurons. Activation of GSK-3beta, in turn, results in modification of the NF-kappaB subunit RelA at serine 468, thereby regulating the physical interaction of RelA with histone deacetylase-3 corepressor molecules. Furthermore, neutralization of Tat or inhibition of GSK-3beta activity prevents neuronal apoptosis induced by HIV-MCM. We conclude that HIV-1 Tat may compromise neuronal function and fate by interfering with normal survival pathways subserved by NF-kappaB. These findings may have important therapeutic implications for the management of HIV-1-associated dementia.
Sui
Ziye
Z
Interdepartmental Program in Neuroscience, University of Rochester School of Medicine and Dentistry, Box 672, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Sniderhan
Lynn F
LF
Fan
Shongshan
S
Kazmierczak
Katarzyna
K
Reisinger
Elizabeth
E
Kovács
Attila D
AD
Potash
Mary Jane
MJ
Dewhurst
Stephen
S
Gelbard
Harris A
HA
Maggirwar
Sanjay B
SB
D015526:AIDS Dementia Complex / Q000378:metabolism / Q000821:virology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004789:Enzyme Activation / Q000502:physiology; D015696:Gene Products, tat / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D015497:HIV-1 / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus
D017077:Culture Media, Conditioned; D015696:Gene Products, tat; D016328:NF-kappa B; D051996:Transcription Factor RelA; D054322:tat Gene Products, Human Immunodeficiency Virus; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D006655:Histone Deacetylases