Tat 101-mediated enhancement of brain pericyte migration involves platelet-derived growth factor subunit B homodimer: Implications for human immunodeficiency virus-associated neurocognitive disorders

Fang Niu, Honghong Yao, Wenting Zhang, Roy Lee Sutliff, Shilpa Buch

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

In the era of antiretroviral therapy, although the human immunodeficiency virus (HIV) replication can be successfully controlled, complications of the CNS continue to affect infected individuals. Viral Tat protein is not only neurotoxic but has also been shown to disrupt the integrity of the blood-brain barrier (BBB). Although the role of brain microvascular endothelial cells and astrocytes in Tat-mediated impairment has been well documented, pericytes, which are important constituents of the BBB and play a key role in maintaining the integrity of the barrier, remain poorly studied in the context of HIV-associated neurocognitive disorders (HAND). In the present study, we demonstrated that exposure of human brain microvascular pericytes and C3H/10T1/2 cells to HIV-1 Tat101 resulted in increased expression of platelet-derived growth factor subunit B homodimer (PDGF-BB) and increased migration of the treated cells. Furthermore, we also demonstrated that this effect of Tat was mediated via activation of mitogen-activated protein kinases and nuclear factor-κB pathways. Secreted PDGF-BB resulted in autocrine activation of the PDGF-BB/PDGF β receptor signaling pathway, culminating ultimately into increased pericyte migration. Ex vivo relevance of these findings was further corroborated in isolated microvessels of HIV Tg26 mice that demonstrated significantly increased expression of PDGF-BB in isolated brain microvessels with a concomitant loss of pericytes. Intriguingly, loss of pericyte coverage was also detected in sections of frontal cortex from humans with HIV-encephalitis compared with the uninfected controls. These findings thus implicate a novel role of PDGF-BB in the migration of pericytes, resulting in loss of pericyte coverage from the endothelium with a subsequent breach of the BBB.

Original languageEnglish (US)
Pages (from-to)11812-11825
Number of pages14
JournalJournal of Neuroscience
Volume34
Issue number35
DOIs
StatePublished - Aug 27 2014

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Keywords

  • BBB
  • HIV Tat
  • PDGF-BB
  • Pericytes

ASJC Scopus subject areas

  • Neuroscience(all)

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