title: Platelet-activating factor receptor activation. An initiator step in HIV-1 neuropathogenesis.
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.
authors.affiliation: Department of Neurology (Child Neurology Division), the University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Perry
authors.forename: J A
authors.initials: JA
authors.lastname: Hamilton
authors.forename: L W
authors.initials: LW
authors.lastname: Tjoelker
authors.forename: G
authors.initials: G
authors.lastname: Dbaibo
authors.forename: K A
authors.initials: KA
authors.lastname: Dzenko
authors.forename: L G
authors.initials: LG
authors.lastname: Epstein
authors.forename: Y
authors.initials: Y
authors.lastname: Hannun
authors.forename: J S
authors.initials: JS
authors.lastname: Whittaker
authors.forename: S
authors.initials: S
authors.lastname: Dewhurst
authors.forename: H A
authors.initials: HA
authors.lastname: Gelbard
mesh_terms: 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
chemical_list: 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