title: TLR3 ligation activates an antiviral response in human fetal astrocytes: a role for viperin/cig5.
abstract: TLR3 functions as a viral nucleic acid sentinel activated by dsRNA viruses and virus replication intermediates within intracellular vesicles. To explore the spectrum of genes induced in human astrocytes by TLR3, we used a microarray approach and the analog polyriboinosinic polyribocytidylic acid (pIC) as ligand. As expected for TLR activation, pIC induced a wide array of cytokines and chemokines known for their role in inflammatory responses, as well as up-regulation of the receptor itself. The data also showed activation of a broad spectrum of antiviral response genes. To determine whether pIC induced an antiviral state in astrocytes, a pseudotyped HIV viral particle, vesicular stomatitis virus g-env-HIV-1, was used. pIC significantly abrogated HIV-1 replication, whereas IL-1, which also potently activates astrocytes, did not. One of the most highly up-regulated genes on microarray was the protein viperin/cig5. We found that viperin/cig5 expression was dependent on IFN regulatory factor 3 and NF-kappaB signaling, and that repetitive stimulation with pIC, but not IL-1, further increased expression. Viperin induction could also be substantially inhibited by neutralizing Abs to IFN-beta, as could HIV-1 replication. To explore a role for viperin in IFN-beta-mediated inhibition of HIV-1, we used an RNA interference (RNAi) approach. RNAi directed against viperin, but not a scrambled RNAi, significantly inhibited viperin expression, and also significantly reversed pIC-induced inhibition of HIV-1 replication. We conclude that viperin contributes to the antiviral state induced by TLR3 ligation in astrocytes, supporting a role for astrocytes as part of the innate immune response against infection in the CNS.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. mriviecc@aecom.yu.edu
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rivieccio
authors.forename: Hyeon-Sook
authors.initials: HS
authors.lastname: Suh
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Meng-Liang
authors.initials: ML
authors.lastname: Zhao
authors.forename: Keh Chuang
authors.initials: KC
authors.lastname: Chin
authors.forename: Sunhee C
authors.initials: SC
authors.lastname: Lee
authors.forename: Celia F
authors.initials: CF
authors.lastname: Brosnan
mesh_terms: D000998:Antiviral Agents / Q000276:immunology*; D001253:Astrocytes / Q000276:immunology* / Q000821:virology*; D015153:Blotting, Western; D018925:Chemokines / Q000378:metabolism; D005333:Fetus; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D016899:Interferon-beta / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011070:Poly I-C / Q000276:immunology*; D011506:Proteins / Q000276:immunology*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014162:Transfection; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D000090123:Viperin Protein
chemical_list: D000998:Antiviral Agents; D018925:Chemokines; D016899:Interferon-beta; D007375:Interleukin-1; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011070:Poly I-C; D011506:Proteins; D034741:RNA, Small Interfering; D051196:Toll-Like Receptor 3; D014759:Viral Envelope Proteins; C495344:TLR3 protein, human; C444427:RSAD2 protein, human; D000090123:Viperin Protein