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J Virol, July 1998, p. 5811-5819, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Rapamycin and Wortmannin Enhance Replication of a Defective Encephalomyocarditis Virus

Yuri V. Svitkin,1 Harry Hahn,2,dagger Anne-Claude Gingras,1 Ann C. Palmenberg,2 and Nahum Sonenberg1,*

Department of Biochemistry and McGill Cancer Center, McGill University, Montreal, Quebec, Canada H3G 1Y6,1 and Institute for Molecular Virology and Department of Animal Health and Biomedical Sciences, University of Wisconsin, Madison, Wisconsin 537062

Received 22 December 1997/Accepted 7 April 1998

Inhibitors of the phosphatidylinositol 3-kinase (PI3 kinase)-FKBP-rapamycin-associated protein (FRAP) pathway, such as rapamycin and wortmannin, induce dephosphorylation and activation of the suppressor of cap-dependent translation, 4E-BP1. Encephalomyocarditis virus (EMCV) infection leads to activation of 4E-BP1 at the time of host translation shutoff. Consistent with these data, rapamycin mildly enhances the synthesis of viral proteins and the shutoff of host cell protein synthesis after EMCV infection. In this study, two defective EMCV strains were generated by deleting portions of the 2A coding region of an infectious cDNA clone. These deletions dramatically decreased the efficiency of viral protein synthesis and abolished the virus-induced shutoff of host translation after infection of BHK-21 cells. Both translation and processing of the P1-2A capsid precursor polypeptide are impaired by the deletions in 2A. The translation and yield of mutant viruses were increased significantly by the presence of rapamycin and wortmannin during infection. Thus, inhibition of the PI3 kinase-FRAP signaling pathway partly complements mutations in 2A protein and reverses a slow-virus phenotype.

* Corresponding author. Mailing address: Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, 3655 Drummond St., Montreal, Quebec, Canada H3G 1Y6. Phone: (514) 398-7274. Fax: (514) 398-1287. E-mail: sonenberg{at}medcor.mcgill.ca.

dagger Present address: Research and Instruction Biocomputer Services, University of California---Los Angeles, Los Angeles, CA 90095-1606.

J Virol, July 1998, p. 5811-5819, Vol. 72, No. 7
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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