HIV-1 gp120 compromises blood-brain barrier integrity and enhance monocyte migration across blood-brain barrier: Implication for viral neuropathogenesis

Georgette D Kanmogne, Kathy Schall, Jessica Leibhart, Bryan Knipe, Howard Eliot Gendelman, Yuri Persidsky

Research output: Contribution to journalArticle

164 Scopus citations

Abstract

Human immunodeficiency virus-1 (HIV-1) encephalitis is characterized by brain infiltration of virus-infected monocytes and macrophages. Cellular products and viral proteins secreted by infected cells likely play an important role in blood-brain barrier (BBB) impairment and the development of HIV-1-associated dementia (HAD). We previously demonstrated that HIV-1 envelope glycoprotein gp120 induces toxicity and alters expression of tight junction proteins in human brain microvascular endothelial cells (HBMECs). Here, we delineate the mechanisms of gp120-induced BBB dysfunction. Human brain microvascular endothelial cells expressed HIV-1 co-receptors (CCR5 and CXCR4). Exposure of HBMECs to gp120 derived from macrophage (CCR5) or lymphocyte (CXCR4)-tropic viruses decreased BBB tightness, increased permeability, and enhanced monocyte migration across in vitro BBB models. Blood-brain barrier integrity was restored after gp120 removal. CCR5 antibodies and inhibitors of myosin light chain kinase or protein kinase C (PKC) blocked gp120-enhanced monocyte migration and permeability of BBB in vitro. Exposure of HBMECs to gp120 induced release of intracellular calcium ([Ca2+]i) that was prevented by CCR5 antibody and partially blocked by CXCR4 antagonist. Human immunodeficiency virus-1 gp120 activated three PKC isoforms in HBMECs [PKC-α/βII, PKC(pan)-βII and PKC-ζ/λ]. Furthermore, specific PKC inhibitors (acting at the ATP-binding and calcium release site) blocked gp120-induced PKC activation and prevented increase in BBB permeability, supporting the biologic significance of these results. Thus, gp120 can cause dysfunction of BBB via PKC pathways and receptor mediated [Ca2+] i release leading to cytoskeletal alterations and increased monocyte migration.

Original languageEnglish (US)
Pages (from-to)123-134
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue number1
DOIs
StatePublished - Jan 5 2007

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Keywords

  • Brain endothelial cells
  • Chemokine receptors
  • HIV-1gp120
  • PKC

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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