TY - JOUR
T1 - TLR3 ligation activates an antiviral response in human fetal astrocytes
T2 - A role for viperin/cig5
AU - Rivieccio, Mark A.
AU - Suh, Hyeon Sook
AU - Zhao, Yongmei
AU - Zhao, Meng Liang
AU - Chin, Keh Chuang
AU - Lee, Sunhee C.
AU - Brosnan, Celia F.
PY - 2006/10/1
Y1 - 2006/10/1
N2 - 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-κB 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-β, as could HIV-1 replication. To explore a role for viperin in IFN-β-mediated inhibition of HIV-1, we used an RNA interference (RNAi) approach. RNAi directed against viperin, bat 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.
AB - 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-κB 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-β, as could HIV-1 replication. To explore a role for viperin in IFN-β-mediated inhibition of HIV-1, we used an RNA interference (RNAi) approach. RNAi directed against viperin, bat 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.
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U2 - 10.4049/jimmunol.177.7.4735
DO - 10.4049/jimmunol.177.7.4735
M3 - Article
C2 - 16982913
AN - SCOPUS:33749129426
SN - 0022-1767
VL - 177
SP - 4735
EP - 4741
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -