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Journal of Virology, October 2007, p. 11246-11255, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01282-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification and Characterization of Interferon-Induced Proteins That Inhibit Alphavirus Replication{triangledown}

Yugen Zhang, Crystal W. Burke, Kate D. Ryman, and William B. Klimstra*

Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130

Received 12 June 2007/ Accepted 30 July 2007

Alpha/beta interferon (IFN-{alpha}/ß) produces antiviral effects through upregulation of many interferon-stimulated genes (ISGs) whose protein products are effectors of the antiviral state. Previous data from our laboratory have shown that IFN-{alpha}/ß can limit Sindbis virus (SB) replication through protein kinase R (PKR)-dependent and PKR-independent mechanisms and that one PKR-independent mechanism inhibits translation of the infecting virus genome (K. D. Ryman et al., J. Virol. 79:1487-1499, 2005). Further, using Affymetrix microarray technology, we identified 44 genes as candidates for PKR/RNase L-independent IFN-induced antiviral activities. In the current studies, we have begun analyzing these gene products for antialphavirus activity using three techniques: (i) overexpression of the protein from SB vectors and assessment of virulence attenuation in mice; (ii) overexpression of the proteins in a stable tetracycline-inducible murine fibroblast culture system and assessment of effects upon SB replication; and (iii) small interfering RNA-mediated knockdown of gene mRNA in fibroblast cultures followed by SB replication assessment as above. Tested proteins included those we hypothesized had potential to affect virus genome translation and included murine ISG20, ISG15, the zinc finger antiviral protein (ZAP), viperin, p56, p54, and p49. Interestingly, the pattern of antiviral activity for some gene products was different between in vitro and in vivo assays. Viperin and ZAP attenuated virulence most profoundly in mice. However, ISG20 and ZAP potently inhibited SB replication in vitro, whereas and viperin, p56, and ISG15 exhibited modest replication inhibition in vitro. In contrast, p54 and p49 had little to no effect in any assay.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130. Phone: (318) 675-5771. Fax: (318) 675-5764. E-mail: wklims{at}lsuhsc.edu

{triangledown} Published ahead of print on 8 August 2007.

Journal of Virology, October 2007, p. 11246-11255, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01282-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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