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Microglia-derived HIV Nef+ exosome impairment of the blood–brain barrier is treatable by nanomedicine-based delivery of Nef peptides
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Microglia-derived HIV Nef+ exosome impairment of the blood–brain barrier is treatable by nanomedicine-based delivery of Nef peptides
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Journal Article
Microglia-derived HIV Nef+ exosome impairment of the blood–brain barrier is treatable by nanomedicine-based delivery of Nef peptides
2016
Overview
The negative factor (Nef) of human immunodeficiency virus (HIV) is an accessory protein that is thought to be integral to HIV-associated immune- and neuroimmune pathogenesis. Here, we show that nef-transfected microglia-released Nef+ exosome (exNef) disrupts the apical blood–brain barrier (BBB) and that only nef-transfected microglia release Nef in exosomes. nef–gfp-transduced neurons and astrocytes release exosomes but did not release exNef in the extracellular space. Apical administration of exNef derived from nef-transfected 293T cells reduced transendothelial electrical resistance (TEER) and increased permeability of the BBB. Microglia-derived exNef applied to either the apical/basal BBB significantly reduced expression of the tight junction protein, ZO-1, suggesting a mechanism of exNef-mediated neuropathogenesis. Microglia exposed to exNef release elevated levels of Toll-like receptor-induced cytokines and chemokines IL-12, IL-8, IL-6, RANTES, and IL-17A. Magnetic nanoparticle delivery of Nef peptides containing the Nef myrisolation site across an in vitro BBB ultimately reduced nef-transfected microglia release of Nef exosomes and prevented the loss of BBB integrity and permeability as measured by TEER and dextran-FITC transport studies, respectively. Overall, we show that exNef is released from nef–gfp-transfected microglia; exNef disrupts integrity and permeability, and tight junctions of the BBB, and induces microglial cytokine/chemokine secretion. These exNef-mediated effects were significantly restricted by Nef peptides. Taken together, this study provides preliminary evidence of the role of exNef in HIV neuroimmune pathogenesis and the feasibility of a nanomedicine-based therapeutics targeting exNef to treat HIV-associated neuropathogenesis.
Publisher
Springer US
Subject
/ Blood-Brain Barrier - drug effects
/ Blood-Brain Barrier - metabolism
/ Drug Carriers - pharmacology
/ Endothelial Cells - cytology
/ Endothelial Cells - drug effects
/ Endothelial Cells - metabolism
/ Escherichia coli - metabolism
/ Green Fluorescent Proteins - genetics
/ Green Fluorescent Proteins - metabolism
/ Human immunodeficiency virus
/ Humans
/ Magnetite Nanoparticles - chemistry
/ nef Gene Products, Human Immunodeficiency Virus - antagonists & inhibitors
/ nef Gene Products, Human Immunodeficiency Virus - genetics
/ nef Gene Products, Human Immunodeficiency Virus - metabolism
/ nef Gene Products, Human Immunodeficiency Virus - pharmacology
/ Peptides - chemical synthesis
/ Virology
