Cross-talk between STAT1 and PI3K/AKT signaling in HIV-1-induced blood-brain barrier dysfunction: Role of CCR5 and implications for viral neuropathogenesis

Bo Yang, Sangya Singh, Rafael Bressani, Georgette D. Kanmogne

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

How neuroinflammation affects signaling pathways leading to human blood-brain barrier (BBB) dysfunction during HIV-1 infection is incompletely understood. We previously demonstrated that signal transducers and activators of transcription-1 (STAT1) signaling is involved in HIV-1 induced BBB damage and is relevant to viral neuropathogenesis. The objective of this study was to delineate the signaling pathways upstream and downstream of STAT1 involved in HIV-1-induced endothelial dysfunction. We show that HIV-1 activation of STAT1 and STAT3 in human brain microvascular endothelial cells (HBMEC) is associated with induction of promoter activity of the interferon-stimulated response element (ISRE)/interferon-γ-activated sequence (GAS). The STAT1 inhibitor fludarabine diminished HIV-1-induced ISRE/GAS promoter activity. CCR5 neutralizing antibodies and the phosphoinositide-3-kinase (PI3K) inhibitor LY-294002 diminished HIV-1-induced phosphorylation of STAT1 and STAT3, significantly diminished HIV-1-induced ISRE/GAS promoter activity, and diminished virus-induced monocyte adhesion and transendothelial migration. HIV-1 infection did not phosphorylate janus kinases but induced activation of the phosphoinositide-dependent kinase-1 (PDK1) and the serine-threonine protein kinase AKT, both downstream effectors of PI3K. CCR5 antibodies also diminished virus-induced phosphorylation ofPDK1 and AKT. These results suggest that the chemokine receptor CCR5 is partially involved in HIV-1 binding to HBMEC and show cross-talk between STAT1 and PI3K pathways in HIV-1-induced BBB dysfunction.

Original languageEnglish (US)
Pages (from-to)3090-3101
Number of pages12
JournalJournal of Neuroscience Research
Volume88
Issue number14
DOIs
StatePublished - Nov 1 2010

Keywords

  • Brain endothelial cell injury
  • CCR5
  • HIV-1
  • PI3K
  • STAT1

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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