title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5800, USA.
authors.forename: Biju
authors.initials: B
authors.lastname: Bhargavan
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5800, USA. gkanmogne@unmc.edu.
authors.forename: Georgette D
authors.initials: GD
authors.lastname: Kanmogne
mesh_terms: D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism / Q000821:virology; D001921:Brain / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D002448:Cell Adhesion; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D015658:HIV Infections / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000821:virology; D015850:Interleukin-6 / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: Blood-brain barrier; CRF02_AG; HIV-1 Tat subtypes; IL-6; JNK/NFκB signaling