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

J Cereb Blood Flow Metab. 2014 Jun;34(6):1047-59. doi: 10.1038/jcbfm.2014.54. Epub 2014 Mar 26.


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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Blood-Brain Barrier / virology
  • Brain / blood supply
  • Brain / metabolism*
  • Brain / virology
  • Cells, Cultured
  • Chemokines / metabolism
  • Collagenases / metabolism
  • Complement C3 / metabolism
  • Complement C7 / metabolism
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Endothelial Cells / virology
  • Female
  • HIV Infections / metabolism*
  • HIV Infections / pathology
  • HIV-1 / metabolism*
  • Humans
  • Male
  • Species Specificity
  • tat Gene Products, Human Immunodeficiency Virus / genetics
  • tat Gene Products, Human Immunodeficiency Virus / metabolism*


  • Chemokines
  • Complement C3
  • Complement C7
  • tat Gene Products, Human Immunodeficiency Virus
  • Collagenases