Differential effects of Tat proteins derived from HIV-1 subtypes B and recombinant CRF02-AG on human brain microvascular endothelial cells: Implications for blood-brain barrier dysfunction

Shawna M. Woollard, Biju Bhargavan, Fang Yu, Georgette D Kanmogne

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18 Citations (Scopus)

Abstract

HIV-1 genetic differences influence viral replication and progression to AIDS. HIV-1 circulating recombinant form (CRF)02-AG is the predominant viral subtype infecting humans in West and Central Africa, but its effects on HIV neuropathogenesis are not known. In the present study, we investigated the effects of Tat proteins from HIV-1 subtype B (Tat.B) and HIV-1 CRF02-AG (Tat.AG) on primary human brain microvascular endothelial cells (HBMEC), the major component of the blood-brain barrier (BBB). Using Affymetrix GeneChip Human Gene 1.0.ST arrays, we showed that Tat.AG had minimal effects while Tat.B induced transcriptional upregulation of 90 genes in HBMEC, including proinflammatory chemokines, complement components C3, C7, and complement factor B, matrix metalloproteinases (MMP)-3, MMP-10, and MMP-12. These results were confirmed by real-time PCR. Compared with Tat.AG, Tat.B significantly increased MMP-3, MMP-10, and MMP-12 activities in HBMEC, and the MMPs tissue inhibitor of metalloproteinase-2 blocked Tat-induced increase in MMPs activity. Western blot analyses also showed that Tat increased the expression of C3 and its cleaved fragment C3b in HBMEC. These data suggest that genetic differences between HIV-1 subtypes B and CRF02-AG influence the effects of Tat proteins from these two clades on HBMEC, including molecular and cellular functions, and canonical pathways, which would affect BBB dysfunction and viral neuropathogenesis.

Original languageEnglish (US)
Pages (from-to)1047-1059
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume34
Issue number6
DOIs
StatePublished - Jun 2014

Fingerprint

tat Gene Products
Blood-Brain Barrier
HIV-1
Endothelial Cells
Brain
Matrix Metalloproteinase 10
Matrix Metalloproteinase 12
Matrix Metalloproteinase 3
Central Africa
Tissue Inhibitor of Metalloproteinase-2
Complement C3
Western Africa
Complement Factor B
Matrix Metalloproteinase Inhibitors
Cellular Structures
Matrix Metalloproteinases
Chemokines
Human Activities
Genes
Real-Time Polymerase Chain Reaction

Keywords

  • HIV-1 CRF02-AG
  • Tat proteins
  • brain endothelium
  • complement
  • matrix metalloproteinases
  • subtype B
  • viral genetic diversity

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Differential effects of Tat proteins derived from HIV-1 subtypes B and recombinant CRF02-AG on human brain microvascular endothelial cells: Implications for blood-brain barrier dysfunction",
abstract = "HIV-1 genetic differences influence viral replication and progression to AIDS. HIV-1 circulating recombinant form (CRF)02-AG is the predominant viral subtype infecting humans in West and Central Africa, but its effects on HIV neuropathogenesis are not known. In the present study, we investigated the effects of Tat proteins from HIV-1 subtype B (Tat.B) and HIV-1 CRF02-AG (Tat.AG) on primary human brain microvascular endothelial cells (HBMEC), the major component of the blood-brain barrier (BBB). Using Affymetrix GeneChip Human Gene 1.0.ST arrays, we showed that Tat.AG had minimal effects while Tat.B induced transcriptional upregulation of 90 genes in HBMEC, including proinflammatory chemokines, complement components C3, C7, and complement factor B, matrix metalloproteinases (MMP)-3, MMP-10, and MMP-12. These results were confirmed by real-time PCR. Compared with Tat.AG, Tat.B significantly increased MMP-3, MMP-10, and MMP-12 activities in HBMEC, and the MMPs tissue inhibitor of metalloproteinase-2 blocked Tat-induced increase in MMPs activity. Western blot analyses also showed that Tat increased the expression of C3 and its cleaved fragment C3b in HBMEC. These data suggest that genetic differences between HIV-1 subtypes B and CRF02-AG influence the effects of Tat proteins from these two clades on HBMEC, including molecular and cellular functions, and canonical pathways, which would affect BBB dysfunction and viral neuropathogenesis.",
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author = "Woollard, {Shawna M.} and Biju Bhargavan and Fang Yu and Kanmogne, {Georgette D}",
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T1 - Differential effects of Tat proteins derived from HIV-1 subtypes B and recombinant CRF02-AG on human brain microvascular endothelial cells

T2 - Implications for blood-brain barrier dysfunction

AU - Woollard, Shawna M.

AU - Bhargavan, Biju

AU - Yu, Fang

AU - Kanmogne, Georgette D

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N2 - HIV-1 genetic differences influence viral replication and progression to AIDS. HIV-1 circulating recombinant form (CRF)02-AG is the predominant viral subtype infecting humans in West and Central Africa, but its effects on HIV neuropathogenesis are not known. In the present study, we investigated the effects of Tat proteins from HIV-1 subtype B (Tat.B) and HIV-1 CRF02-AG (Tat.AG) on primary human brain microvascular endothelial cells (HBMEC), the major component of the blood-brain barrier (BBB). Using Affymetrix GeneChip Human Gene 1.0.ST arrays, we showed that Tat.AG had minimal effects while Tat.B induced transcriptional upregulation of 90 genes in HBMEC, including proinflammatory chemokines, complement components C3, C7, and complement factor B, matrix metalloproteinases (MMP)-3, MMP-10, and MMP-12. These results were confirmed by real-time PCR. Compared with Tat.AG, Tat.B significantly increased MMP-3, MMP-10, and MMP-12 activities in HBMEC, and the MMPs tissue inhibitor of metalloproteinase-2 blocked Tat-induced increase in MMPs activity. Western blot analyses also showed that Tat increased the expression of C3 and its cleaved fragment C3b in HBMEC. These data suggest that genetic differences between HIV-1 subtypes B and CRF02-AG influence the effects of Tat proteins from these two clades on HBMEC, including molecular and cellular functions, and canonical pathways, which would affect BBB dysfunction and viral neuropathogenesis.

AB - HIV-1 genetic differences influence viral replication and progression to AIDS. HIV-1 circulating recombinant form (CRF)02-AG is the predominant viral subtype infecting humans in West and Central Africa, but its effects on HIV neuropathogenesis are not known. In the present study, we investigated the effects of Tat proteins from HIV-1 subtype B (Tat.B) and HIV-1 CRF02-AG (Tat.AG) on primary human brain microvascular endothelial cells (HBMEC), the major component of the blood-brain barrier (BBB). Using Affymetrix GeneChip Human Gene 1.0.ST arrays, we showed that Tat.AG had minimal effects while Tat.B induced transcriptional upregulation of 90 genes in HBMEC, including proinflammatory chemokines, complement components C3, C7, and complement factor B, matrix metalloproteinases (MMP)-3, MMP-10, and MMP-12. These results were confirmed by real-time PCR. Compared with Tat.AG, Tat.B significantly increased MMP-3, MMP-10, and MMP-12 activities in HBMEC, and the MMPs tissue inhibitor of metalloproteinase-2 blocked Tat-induced increase in MMPs activity. Western blot analyses also showed that Tat increased the expression of C3 and its cleaved fragment C3b in HBMEC. These data suggest that genetic differences between HIV-1 subtypes B and CRF02-AG influence the effects of Tat proteins from these two clades on HBMEC, including molecular and cellular functions, and canonical pathways, which would affect BBB dysfunction and viral neuropathogenesis.

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