Abstract
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.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
1-Alkyl-2-acetylglycerophosphocholine Esterase
-
Apoptosis / drug effects
-
Central Nervous System / pathology
-
Central Nervous System / virology*
-
Ceramides / metabolism
-
Culture Media, Conditioned
-
HIV Infections / metabolism*
-
HIV Infections / pathology
-
HIV-1 / pathogenicity*
-
Humans
-
Monocytes / drug effects
-
Monocytes / virology
-
Neurons / drug effects
-
Neurons / virology
-
Phospholipases A / metabolism
-
Platelet Activating Factor / antagonists & inhibitors
-
Platelet Activating Factor / metabolism*
-
Platelet Membrane Glycoproteins / metabolism*
-
Receptors, Cell Surface*
-
Receptors, G-Protein-Coupled*
-
Tumor Cells, Cultured
-
Tumor Necrosis Factor-alpha / pharmacology
Substances
-
Ceramides
-
Culture Media, Conditioned
-
Platelet Activating Factor
-
Platelet Membrane Glycoproteins
-
Receptors, Cell Surface
-
Receptors, G-Protein-Coupled
-
Tumor Necrosis Factor-alpha
-
platelet activating factor receptor
-
Phospholipases A
-
1-Alkyl-2-acetylglycerophosphocholine Esterase