Platelet-activating factor: A candidate human immunodeficiency virus type 1-induced neurotoxin

Harris A. Gelbard, Hans S L M Nottet, Susan Swindells, Marti Jett, Kirk A. Dzenko, Peter Genis, Robert White, Leo Wang, Yun Beom Choi, Dongxian Zhang, Stuart A. Lipton, Wallace W. Tourtellotte, Leon G. Epstein, Howard Eliot Gendelman

Research output: Contribution to journalArticle

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Abstract

The pathogenesis of central nervous system disease during human immunodeficiency virus type 1 (HIV-1) infection revolves around productive viral infection of brain macrophages and microglia. Neuronal losses in the cortex and subcortical gray matter accompany macrophage infection. The question of how viral infection of brain macrophages ultimately leads to central nervous system (CNS) pathology remains unanswered. Our previous work demonstrated high-level production of tumor necrosis factor alpha, interleukin 1β, arachidonic acid metabolites, and platelet-activating factor (PAF) from HIV-infected monocytes and astroglia (H. E. Gendelman, P. Genis, M. Jett, and H. S. L. M. Nottet, in E. Major, ed., Technical Advances in AIDS Research in the Nervous System, in press; P. Genis, M. Jett, E. W. Bernton, H. A. Gelbard, K. Dzenko, R. Keane, L. Resnick, D. J. Volsky, L. G. Epstein, and H. E. Gendelman, J. Exp. Med. 176:1703-1718, 1992). These factors, together, were neurotoxic. The relative role(s) of each of these candidate neurotoxins in HIV-1-related CNS dysfunction was not unraveled by these initial experiments. We now report that PAF is produced during HIV-1-infected monocyte-astroglia interactions. PAF was detected at high levels in CSF of HIV-1-infected patients with immunosuppression and signs of CNS dysfunction. The biologic significance of the results for neurological disease was determined by addition of PAF to cultures of primary human fetal cortical or rat postnatal retinal ganglion neurons. Here, PAF at concentrations of ≥300 pg/ml produced neuronal death. The N-methyl-D-aspartate receptor antagonist MK-801 or memantine partially blocked the neurotoxic effects of PAF. The identification of PAF as an HIV-1-induced neurotoxin provides new insights into how HIV-1 causes neurological impairment and how it may ultimately be ameliorated.

Original languageEnglish (US)
Pages (from-to)4628-4635
Number of pages8
JournalJournal of virology
Volume68
Issue number7
StatePublished - Jul 1 1994

Fingerprint

platelet-activating factor
neurotoxins
Platelet Activating Factor
Neurotoxins
Human immunodeficiency virus 1
HIV-1
Virus Diseases
central nervous system
macrophages
Central Nervous System
astrocytes
Macrophages
Astrocytes
infection
monocytes
Monocytes
Memantine
Retinal Neurons
brain
central nervous system diseases

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Gelbard, H. A., Nottet, H. S. L. M., Swindells, S., Jett, M., Dzenko, K. A., Genis, P., ... Gendelman, H. E. (1994). Platelet-activating factor: A candidate human immunodeficiency virus type 1-induced neurotoxin. Journal of virology, 68(7), 4628-4635.

Platelet-activating factor : A candidate human immunodeficiency virus type 1-induced neurotoxin. / Gelbard, Harris A.; Nottet, Hans S L M; Swindells, Susan; Jett, Marti; Dzenko, Kirk A.; Genis, Peter; White, Robert; Wang, Leo; Choi, Yun Beom; Zhang, Dongxian; Lipton, Stuart A.; Tourtellotte, Wallace W.; Epstein, Leon G.; Gendelman, Howard Eliot.

In: Journal of virology, Vol. 68, No. 7, 01.07.1994, p. 4628-4635.

Research output: Contribution to journalArticle

Gelbard, HA, Nottet, HSLM, Swindells, S, Jett, M, Dzenko, KA, Genis, P, White, R, Wang, L, Choi, YB, Zhang, D, Lipton, SA, Tourtellotte, WW, Epstein, LG & Gendelman, HE 1994, 'Platelet-activating factor: A candidate human immunodeficiency virus type 1-induced neurotoxin', Journal of virology, vol. 68, no. 7, pp. 4628-4635.
Gelbard HA, Nottet HSLM, Swindells S, Jett M, Dzenko KA, Genis P et al. Platelet-activating factor: A candidate human immunodeficiency virus type 1-induced neurotoxin. Journal of virology. 1994 Jul 1;68(7):4628-4635.
Gelbard, Harris A. ; Nottet, Hans S L M ; Swindells, Susan ; Jett, Marti ; Dzenko, Kirk A. ; Genis, Peter ; White, Robert ; Wang, Leo ; Choi, Yun Beom ; Zhang, Dongxian ; Lipton, Stuart A. ; Tourtellotte, Wallace W. ; Epstein, Leon G. ; Gendelman, Howard Eliot. / Platelet-activating factor : A candidate human immunodeficiency virus type 1-induced neurotoxin. In: Journal of virology. 1994 ; Vol. 68, No. 7. pp. 4628-4635.
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