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Journal of Virology, November 2000, p. 10430-10437, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Hepatitis C Virus Internal Ribosome Entry Site (IRES) Stem Loop IIId Contains a Phylogenetically Conserved GGG Triplet Essential for Translation and IRES Folding

Ronald Jubin,1 Nicole E. Vantuno,1 Jeffrey S. Kieft,2 Michael G. Murray,1 Jennifer A. Doudna,2,3 Johnson Y. N. Lau,1 and Bahige M. Baroudy1,*

Department of Antiviral Therapy, Schering-Plough Research Institute, Kenilworth, New Jersey 07033,1 and Department of Molecular Biophysics and Biochemistry3 and Howard Hughes Medical Institute,2 Yale University, New Haven, Connecticut 06520

Received 27 March 2000/Accepted 18 August 2000

The hepatitis C virus (HCV) internal ribosome entry site (IRES) is a highly structured RNA element that directs cap-independent translation of the viral polyprotein. Morpholino antisense oligonucleotides directed towards stem loop IIId drastically reduced HCV IRES activity. Mutagenesis studies of this region showed that the GGG triplet (nucleotides 266 through 268) of the hexanucleotide apical loop of stem loop IIId is essential for IRES activity both in vitro and in vivo. Sequence comparison showed that apical loop nucleotides (UUGGGU) were absolutely conserved across HCV genotypes and the GGG triplet was strongly conserved among related Flavivirus and Pestivirus nontranslated regions. Chimeric IRES elements with IIId derived from GB virus B (GBV-B) in the context of the HCV IRES possess translational activity. Mutations within the IIId stem loop that abolish IRES activity also affect the RNA structure in RNase T1-probing studies, demonstrating the importance of correct RNA folding to IRES function.

* Corresponding author. Mailing address: Antiviral Therapy K-15-4945, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033. Phone: (908) 740-3046. Fax: (908) 740-3918. E-mail: bahige.baroudy{at}spcorp.com.

Journal of Virology, November 2000, p. 10430-10437, Vol. 74, No. 22
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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