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Journal of Virology, April 2006, p. 3147-3156, Vol. 80, No. 7
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.7.3147-3156.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cell-Type-Specific Repression of Internal Ribosome Entry Site Activity by Double-Stranded RNA-Binding Protein 76

Melinda K. Merrill, Elena Y. Dobrikova, and Matthias Gromeier*

Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, North Carolina 27710

Received 21 October 2005/ Accepted 21 December 2005

Translation of picornavirus plus-strand RNA genomes occurs via internal ribosomal entry at highly structured 5' untranslated regions. In addition to canonical translation factors, translation rate is likely influenced by supplementary host and viral trans-acting factors. We previously reported that insertion of a heterologous human rhinovirus type 2 internal ribosomal entry site (IRES) into the poliovirus (PV) genome, generating the chimeric virus PV-RIPO, selectively abrogates viral translation and propagation in neurons, which eliminate poliovirus's signature neuropathogenicity. While severely deficient in cells of neuronal lineage, the rhinovirus IRES promotes efficient propagation of PV-RIPO in cancer cells. Tumor-specific IRES function can be therapeutically exploited to direct viral cytotoxicity to cancer cells. Neuron-glioma heterokaryon analysis implicates neuronal trans-dominant inhibition in this effect, suggesting that host trans-acting factors repress IRES function in a cell-type-specific manner. We identified a set of proteins from neuronal cells with affinity for the rhinovirus IRES, including double-stranded RNA-binding protein 76 (DRBP76). DRBP76 associates with the IRES in neuronal but not in malignant glioma cells. Moreover, DRBP76 depletion in neuronal cells enhances rhinovirus IRES-driven translation and virus propagation. Our observations suggest that cell-type-specific association of DRBP76 with the rhinovirus IRES represses PV-RIPO translation and propagation in neuronal cells.

* Corresponding author. Mailing address: Department of Molecular Genetics & Microbiology, Duke University Medical Center, Box 3020, Durham, NC 27710. Phone: (919) 668-6205. Fax: (919) 684-8735. E-mail: grome001{at}mc.duke.edu.

Journal of Virology, April 2006, p. 3147-3156, Vol. 80, No. 7
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.7.3147-3156.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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