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Journal of Virology, October 2003, p. 10623-10629, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10623-10629.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Significance in Replication of the Terminal Nucleotides of the Flavivirus Genome{dagger}

Alexander A Khromykh,1,2 Natasha Kondratieva,1,2 Jean-Yves Sgro,3 Ann Palmenberg,3 and Edwin G Westaway1,2*

Sir Albert Sakzewski Virus Research Centre, Royal Children's Hospital,1 Clinical Medical Virology Centre, University of Queensland, Brisbane, Queensland, Australia,2 University of Wisconsin, Madison, Wisconsin 537063

Received 14 April 2003/ Accepted 3 July 2003

Point mutations that resulted in a substitution of the conserved 3'-penultimate cytidine in genomic RNA or the RNA negative strand of the self-amplifying replicon of the Flavivirus Kunjin virus completely blocked in vivo replication. Similarly, substitutions of the conserved 3'-terminal uridine in the RNA negative or positive strand completely blocked replication or caused much-reduced replication, respectively. The same preference for cytidine in the 3'-terminal dinucleotide was noted in reports of the in vitro activity of the RNA-dependent RNA polymerase (RdRp) for the other genera of Flaviviridae that also employ a double-stranded RNA (dsRNA) template to initiate asymmetric semiconservative RNA positive-strand synthesis. The Kunjin virus replicon results were interpreted in the context of a proposed model for initiation of RNA synthesis based on the solved crystal structure of the RdRp of {phi}6 bacteriophage, which also replicates efficiently using a dsRNA template with conserved 3'-penultimate cytidines and a 3'-terminal pyrimidine. A previously untested substitution of the conserved pentanucleotide at the top of the 3'-terminal stem-loop of all Flavivirus species also blocked detectable in vivo replication of the Kunjin virus replicon RNA.

* Corresponding author. Mailing address: Sir Albert Sakzewski Virus Research Centre, Royal Children's Hospital, Brisbane, Queensland 4029, Australia. Phone: (617) 3636 1400. Fax: (617) 3636 1401. E-mail: e.westaway{at}mailbox.uq.edu.au.

{dagger} This is publication no. 181 from the Sir Albert Sakzewski Virus Research Centre.

Journal of Virology, October 2003, p. 10623-10629, Vol. 77, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.19.10623-10629.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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