Microglia-derived HIV Nef+ exosome impairment of the blood-brain barrier is treatable by nanomedicine-based delivery of Nef peptides.
J Neurovirol
; 22(2): 129-39, 2016 Apr.
Article
en En
| MEDLINE
| ID: mdl-26631079
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Péptidos
/
Portadores de Fármacos
/
Microglía
/
Productos del Gen nef del Virus de la Inmunodeficiencia Humana
/
Exosomas
Tipo de estudio:
Prognostic_studies
Aspecto:
Implementation_research
Límite:
Humans
Idioma:
En
Revista:
J Neurovirol
Asunto de la revista:
NEUROLOGIA
/
VIROLOGIA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos