HIV-1 induces cytoskeletal alterations and Rac1 activation during monocyte-blood-brain barrier interactions: modulatory role of CCR5

• Published in: Retrovirology 2014-02, Vol.11 (1), p.20-20, Article 20
• Main Authors: Woollard, Shawna M, Li, Hong, Singh, Sangya, Yu, Fang, Kanmogne, Georgette D
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adult; Aged; AIDS; Antibodies; Blood-Brain Barrier; Brain research; Cell Adhesion; Colleges & universities; Comparative analysis; Cytoskeletal proteins; Cytoskeleton - metabolism; Cytotoxicity; Endothelial Cells - physiology; Endothelium; Ethics; Experiments; Female; HIV; HIV-1 - physiology; Host-Pathogen Interactions; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Infections; Integrins; Macrophages; Male; Medical research; Medicine, Experimental; Middle Aged; Monocytes - physiology; Monocytes - virology; Motility; Neurosciences; Physiological aspects; Proteins; rac1 GTP-Binding Protein - metabolism; Receptors, CCR5 - metabolism; Viral antibodies; Viral infections
• ISSN: 1742-4690; 1742-4690
• DOI: 10.1186/1742-4690-11-20

Most HIV strains that enter the brain are macrophage-tropic and use the CCR5 receptor to bind and infect target cells. Because the cytoskeleton is a network of protein filaments involved in cellular movement and migration, we investigated whether CCR5 and the cytoskeleton are involved in endothelial-mononuclear phagocytes interactions, adhesion, and HIV-1 infection. Using a cytoskeleton phospho-antibody microarray, we showed that after co-culture with human brain microvascular endothelial cells (HBMEC), HIV-1 infected monocytes increased expression and activation of cytoskeleton-associated proteins, including Rac1/cdc42 and cortactin, compared to non-infected monocytes co-cultured with HBMEC. Analysis of brain tissues from HIV-1-infected patients validated these findings, and showed transcriptional upregulation of Rac1 and cortactin, as well as increased activation of Rac1 in brain tissues of HIV-1-infected humans, compared to seronegative individuals and subjects with HIV-1-encephalitis. Confocal imaging showed that brain cells expressing phosphorylated Rac1 were mostly macrophages and blood vessels. CCR5 antagonists TAK-799 and maraviroc prevented HIV-induced upregulation and phosphorylation of cytoskeleton-associated proteins, prevented HIV-1 infection of macrophages, and diminished viral-induced adhesion of monocytes to HBMEC. Ingenuity pathway analysis suggests that during monocyte-endothelial interactions, HIV-1 alters protein expression and phosphorylation associated with integrin signaling, cellular morphology and cell movement, cellular assembly and organization, and post-translational modifications in monocytes. CCR5 antagonists prevented these HIV-1-induced alterations. HIV-1 activates cytoskeletal proteins during monocyte-endothelial interactions and increase transcription and activation of Rac1 in brain tissues. In addition to preventing macrophage infection, CCR5 antagonists could diminish viral-induced alteration and phosphorylation of cytoskeletal proteins, monocyte adhesion to the brain endothelium and viral entry into the central nervous system.