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Journal of Virology, February 2005, p. 1487-1499, Vol. 79, No. 3
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.3.1487-1499.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Sindbis Virus Translation Is Inhibited by a PKR/RNase L-Independent Effector Induced by Alpha/Beta Interferon Priming of Dendritic Cells

Department of Microbiology and Immunology, Center for Molecular and Tumor Virology,¹ Department of Biochemistry, Louisiana State University Health Sciences Center, Shreveport, Louisiana,² Rockefeller University, New York, New York³

Received 4 August 2004/ Accepted 15 September 2004

The tropism of Sindbis virus (SB) for cells of the dendritic cell (DC) lineage and the virulence of SB in vivo are largely determined by the efficacy of alpha/beta interferon (IFN-/ß)-mediated antiviral responses. These responses are essentially intact in the absence of PKR and/or RNase L (K. D. Ryman, L. J. White, R. E. Johnston, and W. B. Klimstra, Viral Immunol. 15:53-76, 2002). In the present studies, we investigated the nature of antiviral effects and identity of antiviral effectors primed by IFN-/ß treatment of bone marrow-derived DCs (BMDCs) generated from mice deficient in PKR and RNase L (TD). IFN-/ß priming exerted significant antiviral activity at very early stages of SB replication and most likely inhibited the initial translation of infecting genomes. The early effect targeted cap-dependent translation as protein synthesis from an SB-like and a simple RNA were inhibited by interferon treatment, but an encephalomyocarditis virus internal ribosome entry site-driven element exhibited no inhibition. Phosphorylation of the subunit of eukaryotic translation initiation factor 2 was defective after virus infection of TD cells, suggesting other mechanisms of translation inhibition. To identify components of these alternative antiviral pathway(s), we have compared global gene regulation in BMDCs derived from normal 129 Sv/Ev, IFNAR1^–/–, and TD mice following infection with SB or treatment with IFN-/ß. Candidate effectors of alternative antiviral pathways were those genes induced by virus infection or IFN-/ß treatment in 129 Sv/Ev and TD-derived BMDC but not in virus-infected or IFN-/ß-treated IFNAR1^–/– cells. Statistical analyses of gene array data identified 44 genes that met these criteria which are discussed.

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