Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia

Jialin Zheng, Michael R. Thylin, Anuja Ghorpade, Huangui Xiong, Yuri Persidsky, Robin Cotter, Douglas Niemann, Myhanh Che, Yong Chun Zeng, Harris A. Gelbard, Robin B. Shepard, Jennifer M. Swartz, Howard E. Gendelman

Research output: Contribution to journalArticle

262 Scopus citations

Abstract

The mechanism(s) by which HIV-1 affects neural injury in HIV-1-associated dementia (HAD) remains unknown. To ascertain the role that cellular and viral macrophage products play in HAD neurotoxicity, we explored one potential route for neuronal demise, CXCR4. CXCR4, expressed on lymphocytes and neurons, is both a part of neural development and a co-receptor for HIV-1. Its ligand, stromal cell-derived factor-1α (SDF-1α), affects neuronal viability. GTP binding protein (G-protein) linked signaling after neuronal exposure to SDF-1α, virus-infected monocyte-derived macrophage (MDM) secretory products, and virus was determined. In both human and rat neurons, CXCR4 was expressed at high levels. SDF-1α/β was detected predominantly in astrocytes and at low levels in MDM. SDF-1α/β was expressed in HAD brain tissue and upregulated in astrocytes exposed to virus infected and/or immune activated MDM conditioned media (fluids). HIV-1-infected MDM secretions, virus and SDF-1α induced a G inhibitory (Gi) protein-linked decrease in cyclic AMP (cAMP) and increase inositol 1,4, 5-trisphosphate (IP3) and intracellular calcium. Such effects were partially blocked by antibodies to CXCR4 or removal of virus from MDM fluids. Changes in G-protein-coupled signaling correlated, but were not directly linked, to increased neuronal synaptic transmission, Caspase 3 activation and apoptosis. These data, taken together, suggest that CXCR4-mediated signal transduction may be a potential mechanism for neuronal dysfunction during HAD. Copyright (C) 1999 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)185-200
Number of pages16
JournalJournal of Neuroimmunology
Volume98
Issue number2
DOIs
StatePublished - Aug 3 1999

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Keywords

  • CXCR4
  • GTP binding protein
  • HIV-1 associated dementia
  • Monocyte-derived macrophages
  • Neuronal apoptosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

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