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J Biol Chem, Vol. 273, Issue 28, 17660-17664, July 10, 1998

Platelet-activating Factor Receptor Activation
AN INITIATOR STEP IN HIV-1 NEUROPATHOGENESIS

From the Departments of ^a Neurology (Child Neurology Division), ^e Pediatrics, ^f Microbiology and Immunology, ^h Pharmacology and Physiology, the University of Rochester Medical Center, Rochester, New York 14642, ^b ICOS Corporation, Seattle, Washington 98021, the ^c Department of Pediatrics, The American University of Beirut, Beirut, Lebanon, the ^d Department of Pharmacology, University of Connecticut, Farmington, Connecticut 06030, and the ^g Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

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

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