Differential Mechanisms of Inflammation and Endothelial Dysfunction by HIV-1 Subtype-B and Recombinant CRF02_AG Tat Proteins on Human Brain Microvascular Endothelial Cells: Implications for Viral Neuropathogenesis

Mol Neurobiol. 2018 Feb;55(2):1352-1363. doi: 10.1007/s12035-017-0382-0. Epub 2017 Jan 27.


The recombinant HIV-1 CRF02_AG is prevalent in West-Central Africa but its effects on the blood-brain barrier (BBB) and HIV-associated neurocognitive disorders (HAND) are not known. We analyzed the effects of Tat from HIV-1 subtype-B (Tat.B) and CRF02_AG (Tat.AG) on primary human brain microvascular endothelial cells (HBMEC), the major BBB component. Exposure of HBMEC to Tat.B increased IL-6 expression and transcription by 9- (P < 0.001) and 113-fold (P < 0.001), respectively, whereas Tat.AG increased IL-6 expression and transcription by 2.7-3.8-fold and 35.7-fold (P < 0.001), respectively. Tat.B induced IL-6 through the interleukin-1 receptor-associated kinase (IRAK)-1/4/mitogen-activated protein kinase kinase(MKK)/C-jun N-terminal kinase(JNK) pathways, in an activator protein-1(AP1)- and nuclear factor-kappaB (NFκB)-independent manner, whereas Tat.AG effects occurred via MKK/JNK/AP1/NFκB pathways. Tat-induced effects were associated with activation of c-jun (serine-63) and SAPK/JNK (Thr183/Tyr185). We demonstrated increased expression of transcription factors associated with these pathways (Jun, RELB, CEBPA), with higher levels in Tat.B-treated cells compared to Tat.AG. Functional studies showed that Tat.B and Tat.AG decreased the expression of tight junction proteins claudin-5 and ZO-1 and decreased the trans-endothelial electric resistance (TEER); Tat.B induced greater reduction in TEER, claudin-5, and ZO-1, compared to Tat.AG. Overall, our data showed increased inflammation and BBB dysfunction with Tat.B, compared to Tat.AG. This suggests these two HIV-1 subtypes differentially affect the BBB and central nervous system; our data provides novel insights into the molecular basis of these differential Tat-mediated effects.

Keywords: Blood-brain barrier; CRF02_AG; HIV-1 Tat subtypes; IL-6; JNK/NFκB signaling.

Publication types

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

MeSH terms

  • Blood-Brain Barrier / cytology
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / virology
  • Brain / cytology
  • Brain / metabolism*
  • Brain / virology
  • Cell Adhesion
  • Cell Movement / physiology
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Endothelial Cells / virology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / virology
  • HIV Infections / metabolism
  • Humans
  • Inflammation / metabolism*
  • Inflammation / virology
  • Interleukin-6 / metabolism
  • Monocytes / cytology
  • Monocytes / metabolism
  • Monocytes / virology
  • tat Gene Products, Human Immunodeficiency Virus / metabolism*


  • Interleukin-6
  • tat Gene Products, Human Immunodeficiency Virus