title: Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation.
abstract: HIV invades the brain early after infection; however, its interactions with the cells of the blood-brain barrier (BBB) remain poorly understood. Our goal was to evaluate the role of occludin, one of the tight junction proteins that regulate BBB functions in HIV infection of BBB pericytes. We provide evidence that occludin levels largely control the metabolic responses of human pericytes to HIV. Occludin in BBB pericytes decreased by 10% during the first 48 h after HIV infection, correlating with increased nuclear translocation of the gene repressor C-terminal-binding protein (CtBP)-1 and NFκB-p65 activation. These changes were associated with decreased expression and activation of the class III histone deacetylase sirtuin (SIRT)-1. Occludin levels recovered 96 h after infection, restoring SIRT-1 and reducing HIV transcription to 20% of its highest values. We characterized occludin biochemically as a novel NADH oxidase that controls the expression and activation of SIRT-1. The inverse correlation between occludin and HIV transcription was then replicated in human primary macrophages and differentiated monocytic U937 cells, in which occludin silencing resulted in 75 and 250% increased viral transcription, respectively. Our work shows that occludin has previously unsuspected metabolic properties and is a target of HIV infection, opening the possibility of designing novel pharmacological approaches to control HIV transcription.
authors.affiliation: *Department of Biochemistry and Molecular Biology and Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Biology, Freie Universität Berlin, Berlin, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany vcastrovillela@med.miami.edu mtoborek@med.miami.edu iblasig@fmp-berlin.de.
authors.forename: Victor
authors.initials: V
authors.lastname: Castro
authors.affiliation: *Department of Biochemistry and Molecular Biology and Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Biology, Freie Universität Berlin, Berlin, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
authors.affiliation: *Department of Biochemistry and Molecular Biology and Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Biology, Freie Universität Berlin, Berlin, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Mareen
authors.initials: M
authors.lastname: Luethen
authors.affiliation: *Department of Biochemistry and Molecular Biology and Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Biology, Freie Universität Berlin, Berlin, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Dabrowski
authors.affiliation: *Department of Biochemistry and Molecular Biology and Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Biology, Freie Universität Berlin, Berlin, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Lombardi
authors.affiliation: *Department of Biochemistry and Molecular Biology and Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Biology, Freie Universität Berlin, Berlin, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Morgan
authors.affiliation: *Department of Biochemistry and Molecular Biology and Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Biology, Freie Universität Berlin, Berlin, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Sharova
authors.affiliation: *Department of Biochemistry and Molecular Biology and Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Biology, Freie Universität Berlin, Berlin, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Stevenson
authors.affiliation: *Department of Biochemistry and Molecular Biology and Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Biology, Freie Universität Berlin, Berlin, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany vcastrovillela@med.miami.edu mtoborek@med.miami.edu iblasig@fmp-berlin.de.
authors.forename: Ingolf E
authors.initials: IE
authors.lastname: Blasig
authors.affiliation: *Department of Biochemistry and Molecular Biology and Division of Infectious Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA; Department of Biology, Freie Universität Berlin, Berlin, Germany; and Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany vcastrovillela@med.miami.edu mtoborek@med.miami.edu iblasig@fmp-berlin.de.
authors.forename: Michal
authors.initials: M
authors.lastname: Toborek
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000821:virology*; D001921:Brain / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D006678:HIV / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism / Q000821:virology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D062793:Occludin / Q000378:metabolism*; D020286:Pericytes / Q000378:metabolism / Q000821:virology; D056564:Sirtuin 1 / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000821:virology; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D016328:NF-kappa B; C568985:OCLN protein, human; D062793:Occludin; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: NADH oxidase; blood–brain barrier; human macrophage; metabolic regulation; tight junction protein