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TLR3 Ligation Activates an Antiviral Response in Human Fetal Astrocytes: A Role for Viperin/cig5¹

Mark A. Rivieccio^2,3,*, Hyeon-Sook Suh^2,*, Yongmei Zhao^*, Meng-Liang Zhao^*, Keh Chuang Chin, Sunhee C. Lee^* and Celia F. Brosnan^*,

^* Department of Pathology and Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461; and Genome Institute of Singapore, Singapore

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-B 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-, as could HIV-1 replication. To explore a role for viperin in IFN--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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 NS040137 and MH55477, Neuropathology Training Grant T32 NS007098, and Einstein Center for AIDS Research Grant P30 AI051519.

² M.A.R. and H.-S.S. are cofirst authors.

³ Address correspondence and reprint requests to Dr. Mark A. Rivieccio, Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. E-mail address: mriviecc{at}aecom.yu.edu

⁴ Abbreviations used in this paper: IRF3, IFN regulatory factor 3; pIC, polyriboinosinic polyribocytidylic acid; siRNA, small interfering RNA; Q-PCR, quantitative PCR; A.U., arbitrary unit; iNOS, inducible NO synthase; IHC, immunohistochemistry; OAS, oligoadenylate synthetase; CHX, cycloheximide; TTX-100, Triton X-100; VSV, vesicular stomatitis virus; NMMA, N-monomethyl L-arginine; PKR, dsRNA-dependent protein kinase; 2-AP, 2-aminopurine; WNV, West Nile virus; ISG, IFN-stimulated gene.

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