Platelet-activating factor receptor activation. An initiator step in HIV-1 neuropathogenesis

Seth W. Perry, Jason A. Hamilton, Larry W. Tjoelker, Ghassan Dbaibo, Kirk A. Dzenko, Leon G. Epstein, Yusuf Hannun, J. Steven Whittaker, Stephen Dewhurst, Harris A. Gelbard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

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-α (TNF-α) and the phospholipid mediator platelet-activating factor (PAF). TNF-α 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- α-induced increase in neuronal ceramide levels. TNF-α-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.

Original languageEnglish (US)
Pages (from-to)17660-17664
Number of pages5
JournalJournal of Biological Chemistry
Volume273
Issue number28
DOIs
StatePublished - Jul 10 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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