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Journal of Virology, August 2007, p. 8396-8405, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00321-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Genetic Adaptation to Untranslated Region-Mediated Enterovirus Growth Deficits by Mutations in the Nonstructural Proteins 3AB and 3CD{triangledown}

Paola Florez de Sessions, Elena Dobrikova, and Matthias Gromeier*

Division of Neurological Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710

Received 13 February 2007/ Accepted 22 May 2007

Both untranslated regions (UTRs) of plus-strand RNA virus genomes jointly control translation and replication of viral genomes. In the case of the Enterovirus genus of the Picornaviridae family, the 5'UTR consists of a cloverleaf-like terminus preceding the internal ribosomal entry site (IRES) and the 3' terminus is composed of a structured 3'UTR and poly(A). The IRES and poly(A) have been implicated in translation control, and all UTR structures, in addition to cis-acting genetic elements mapping to the open reading frame, have been assigned roles in RNA replication. Viral UTRs are recognized by viral and host cell RNA-binding proteins that may codetermine genome stability, translation, plus- and minus-strand RNA replication, and scaffolding of viral replication complexes within host cell substructures. In this report, we describe experiments with coxsackie B viruses with a cell type-specific propagation deficit in Sk-N-Mc neuroblastoma cells conferred by the combination of a heterologous IRES and altered 3'UTR. Serial passage of these constructs in Sk-N-Mc cells yielded genetic adaptation by mutations within the viral nonstructural proteins 3A and 3C. Our data implicate 3A and/or 3C or their precursors 3AB and/or 3CD in a functional complex with the IRES and 3'UTR that drives viral propagation. Adaptation to neuroblastoma cells suggests an involvement of cell type-specific host factors or the host cell cytoplasmic milieu in this phenomenon.

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

{triangledown} Published ahead of print on 30 May 2007.

Journal of Virology, August 2007, p. 8396-8405, Vol. 81, No. 16
0022-538X/07/$08.00+0     doi:10.1128/JVI.00321-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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