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

• Published in: Journal of cerebral blood flow and metabolism 2007-01, Vol.27 (1), p.123
• Main Authors: Kanmogne, Georgette D, Schall, Kathy, Leibhart, Jessica, Knipe, Bryan, Gendelman, Howard E, Persidsky, Yuri
• Format: Article
• Language: English
• Subjects: Blood-Brain Barrier - drug effects; Blotting, Western; Calcium - metabolism; Cell Membrane Permeability - drug effects; Cell Movement - drug effects; Cells, Cultured; Electric Impedance; Endothelial Cells - drug effects; Endothelial Cells - pathology; Endothelium, Vascular - physiology; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; HIV Envelope Protein gp120 - metabolism; HIV Envelope Protein gp120 - toxicity; HIV Infections - pathology; Humans; Isoenzymes - metabolism; Microscopy, Fluorescence; Monocytes - drug effects; Nerve Tissue Proteins - metabolism; Neurons - pathology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Receptors, CCR5 - physiology; Receptors, CXCR4 - physiology
• ISSN: 0271-678X

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 ([Ca(2+)](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-alpha/betaII, PKC(pan)-betaII and PKC-zeta/lambda]. 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 [Ca(2+)](i) release leading to cytoskeletal alterations and increased monocyte migration.