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Vol. 17, Issue 11, 4632-4644, November 2006

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Initiation of Protein Synthesis by Hepatitis C Virus Is Refractory to Reduced eIF2 · GTP · Met-tRNA_i^Met Ternary Complex Availability

Francis Robert^*, Lee D. Kapp, Shakila N. Khan^*, Michael G. Acker, Sarah Kolitz, Shirin Kazemi, Randal J. Kaufman^,||, William C. Merrick^¶, Antonis E. Koromilas, Jon R. Lorsch, and Jerry Pelletier^*,#

*Department of Biochemistry and ^#McGill Cancer Center, McGill University, Montreal, Quebec, Canada H3G 1Y6; Department of Biophysics and Biophysical Chemistry, John Hopkins University School of Medicine, Baltimore, MD 21205-2185; Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2; Howard Hughes Medical Institute and ^||Departments of Biological Chemistry and Internal Medicine, University of Michigan, Ann Arbor, MI 48109; and ^¶Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4935

Submitted June 1, 2006; Revised August 4, 2006; Accepted August 14, 2006
Monitoring Editor: Sandra Schmid

A cornerstone of the antiviral interferon response is phosphorylation of eukaryotic initiation factor (eIF)2. This limits the availability of eIF2·GTP·Met-tRNA_i^Met ternary complexes, reduces formation of 43S preinitiation complexes, and blocks viral (and most cellular) mRNA translation. However, many viruses have developed counterstrategies that circumvent this cellular response. Herein, we characterize a novel class of translation initiation inhibitors that block ternary complex formation and prevent the assembly of 43S preinitiation complexes. We find that translation driven by the HCV IRES is refractory to inhibition by these compounds at concentrations that effectively block cap-dependent translation in vitro and in vivo. Analysis of initiation complexes formed on the HCV IRES in the presence of inhibitor indicates that eIF2 and Met-tRNA_i^Met are present, defining a tactic used by HCV to evade part of the antiviral interferon response.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-06-0478) on August 23, 2006.

Address correspondence to: Jerry Pelletier (jerry.pelletier{at}mcgill.ca)

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