Dataset Information

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

ABSTRACT:

Background

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.

Results

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.

Conclusions

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.

SUBMITTER: Woollard SM

PROVIDER: S-EPMC4015682 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Woollard Shawna M SM Li Hong H Singh Sangya S Yu Fang F Kanmogne Georgette D GD

Retrovirology 20140226

<h4>Background</h4>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.<h4>Results</h4>Using a cytoskeleton phospho-antibody microarray, we showed that after co-culture with human brai ...[more]

PMID: 24571616

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Dataset Information

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

Background

Results

Conclusions

Publications

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

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