Human immunodeficiency virus-1/surface glycoprotein 120 induces apoptosis through RNA-activated protein kinase signaling in neurons.
Previous work has demonstrated that the surface glycoprotein (gp120) of human immunodeficiency virus-1 (HIV-1) can induce damage and apoptosis of neurons both in vitro and in vivo. In this report, we provide evidence that double-stranded RNA-activated protein kinase (PKR), a stress kinase, is involved in HIV/gp120-associated neurodegeneration. In cultures of mixed cortical cells, HIV/gp120 increased the protein level of PKR. Additionally, PKR was phosphorylated in neurons but not glia after exposure to gp120. The use of two independent pharmacological inhibitors of PKR activity abrogated neuronal cell death induced by gp120. Cortical neurons from PKR knock-out mice were significantly protected from neurotoxicity induced by gp120, further validating the pivotal proapoptotic function of PKR. gp120-induced phosphorylated PKR localized prominently to neuronal nuclei; PKR inhibition or the NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate] abrogated this effect. PKR inactivation also inhibited gp120-induced caspase-3 activation, consistent with its neuroprotective effect. Finally, brain tissue from individuals diagnosed with HIV-associated dementia (HAD), but not HIV infection alone, contained the activated form of PKR, which localized predominantly to neuronal nuclei. Together, these results identify PKR as a critical mediator of gp120 neurotoxicity, suggesting that activation of PKR contributes to the neuronal injury and cell death observed in HAD.
Alirezaei
Mehrdad
M
Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037, USA.
Watry
Debbie D
DD
Flynn
Claudia F
CF
Kiosses
William B
WB
Masliah
Eliezer
E
Williams
Bryan R G
BR
Kaul
Marcus
M
Lipton
Stuart A
SA
Fox
Howard S
HS
D015526:AIDS Dementia Complex / Q000201:enzymology / Q000473:pathology / Q000821:virology; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology* / Q000473:pathology / Q000821:virology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D019892:eIF-2 Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D015699:HIV Envelope Protein gp120; D019892:eIF-2 Kinase