Platelet-activating factor receptor activation. An initiator step in HIV-1 neuropathogenesis.
Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system results in neuronal apoptosis. Activated HIV-1-infected monocytes secrete high levels of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and the phospholipid mediator platelet-activating factor (PAF). TNF-alpha and PAF are elevated in the central nervous system of patients with HIV-1-associated dementia. We now demonstrate that conditioned media from activated HIV-1-infected monocytes induces neuronal apoptosis, which can be prevented by co-incubation with PAF acetylhydrolase, the enzyme that catabolizes PAF in the central nervous system. Preceding apoptosis is a TNF-alpha-induced increase in neuronal ceramide levels. TNF-alpha-mediated neuronal apoptosis can also be blocked by co-incubation with PAF acetylhydrolase, or a PAF receptor antagonist. Blocking pathologic activation of PAF receptors may therefore be a pivotal step in the treatment of HIV-1-associated dementia.
Perry
S W
SW
Department of Neurology (Child Neurology Division), the University of Rochester Medical Center, Rochester, New York 14642, USA.
Hamilton
J A
JA
Tjoelker
L W
LW
Dbaibo
G
G
Dzenko
K A
KA
Epstein
L G
LG
Hannun
Y
Y
Whittaker
J S
JS
Dewhurst
S
S
Gelbard
H A
HA
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D017209:Apoptosis / Q000187:drug effects; D002490:Central Nervous System / Q000473:pathology / Q000821:virology*; D002518:Ceramides / Q000378:metabolism; D017077:Culture Media, Conditioned; D015658:HIV Infections / Q000378:metabolism* / Q000473:pathology; D015497:HIV-1 / Q000472:pathogenicity*; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000821:virology; D009474:Neurons / Q000187:drug effects / Q000821:virology; D010741:Phospholipases A / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002518:Ceramides; D017077:Culture Media, Conditioned; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase