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Topics {✒️}

nef-gfp-transfected chme-5 cells month download article/chapter apical blood–brain barrier blood-brain barrier disruption nef–gfp-transfected microglia human immunodeficiency virus microglia-derived exnef applied blood–brain barrier dextran-fitc transport studies grant awards 3r01da027049-04s1 nef–gfp-transduced neurons primary human monocyte/macrophages full article pdf hiv-1 nef induces soluble nef antigen ap-1 transcription factors microglial cells hiv-1 protein nef hiv-1 nef protein nef-dependent induction privacy choices/manage cookies magnetic nanoparticle delivery blood transfusion donor campbell-sims tc hiv-1-infected cells human monocyte/macrophages hiv-1 nef employs unprimed human cd4+ astrocytes release exosomes nef endocytotic signals nef activates stat3 nef domains interacting nanomedicine-based delivery hiv-infected individuals related subjects pi3k/akt pathway endosomal-exosomal pathway deliver small rna vitro cytocidal effects receptor-induced cytokines nef increases infectivity cell endocytotic machinery nef peptides published article journal tight junction protein nef myrisolation site greenway al european economic area scope submit manuscript vesicle

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         headline:Microglia-derived HIV Nef+ exosome impairment of the blood–brain barrier is treatable by nanomedicine-based delivery of Nef peptides
         description: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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      name:Institute of Neuroimmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, USA
      name:Institute of Neuroimmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, USA
      name:Institute of Neuroimmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, USA
      name:Institute of Neuroimmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, USA
      name:Department of Mechanical and Materials Engineering, College of Engineering and Computing, Florida International University, Miami, USA
      name:Institute of Neuroimmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, USA
      name:Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, USA
      name:Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami, USA
      name:Institute of Neuroimmune Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, USA
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