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Erschienen in:

01.04.2016

Microglia-derived HIV Nef+ exosome impairment of the blood–brain barrier is treatable by nanomedicine-based delivery of Nef peptides

verfasst von: A. D. Raymond, P. Diaz, S. Chevelon, M. Agudelo, A. Yndart-Arias, H. Ding, A. Kaushik, R. Dev Jayant, R. Nikkhah-Moshaie, U. Roy, S. Pilakka-Kanthikeel, M. P. Nair

Erschienen in: Journal of NeuroVirology | Ausgabe 2/2016

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Abstract

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.

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Titel: Microglia-derived HIV Nef+ exosome impairment of the blood–brain barrier is treatable by nanomedicine-based delivery of Nef peptides
verfasst von: A. D. Raymond
P. Diaz
S. Chevelon
M. Agudelo
A. Yndart-Arias
H. Ding
A. Kaushik
R. Dev Jayant
R. Nikkhah-Moshaie
U. Roy
S. Pilakka-Kanthikeel
M. P. Nair
Publikationsdatum: 01.04.2016
Verlag: Springer US
Erschienen in: Journal of NeuroVirology / Ausgabe 2/2016
Print ISSN: 1355-0284
Elektronische ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-015-0397-0

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