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Journal of Virology, April 2006, p. 4099-4113, Vol. 80, No. 8
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.8.4099-4113.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Functional Analysis of the Tick-Borne Encephalitis Virus Cyclization Elements Indicates Major Differences between Mosquito-Borne and Tick-Borne Flaviviruses

Regina M. Kofler,1 Verena M. Hoenninger,1 Caroline Thurner,2 and Christian W. Mandl1*

Clinical Institute of Virology, Medical University of Vienna,1 Institute for Theoretical Chemistry, University of Vienna, Vienna, Austria2

Received 17 November 2005/ Accepted 18 January 2006

The linear, positive-stranded RNA genome of flaviviruses is thought to adopt a circularized conformation via interactions of short complementary sequence elements located within its terminal regions. This process of RNA cyclization is a crucial precondition for RNA replication. In the case of mosquito-borne flaviviruses, highly conserved cyclization sequences (CS) have been identified, and their functionality has been experimentally confirmed. Here, we provide an experimental identification of CS elements of tick-borne encephalitis virus (TBEV). These elements, termed 5'-CS-A and 3'-CS-A, are conserved among various tick-borne flaviviruses, but they are unrelated to the mosquito-borne CS elements and are located at different genomic positions. The 5'-CS-A element is situated upstream rather than downstream of the AUG start codon and, in contrast to mosquito-borne flaviviruses, it was found that the entire protein C coding region is not essential for TBEV replication. The complementary 3'-CS-A element is located within the bottom stem rather than upstream of the characteristic 3'-terminal stem-loop structure, implying that this part of the proposed structure cannot be formed when the genome is in its circularized conformation. Finally, we demonstrate that the CS-A elements can also mediate their function when the 5'-CS-A element is moved from its natural position to one corresponding to the mosquito-borne CS. The recognition of essential RNA elements and their differences between mosquito-borne and tick-borne flaviviruses has practical implications for the design of replicons in vaccine and vector development.

* Corresponding author. Mailing address: Clinical Institute of Virology, Medical University of Vienna, Kinderspitalgasse 15, A-1095 Vienna, Austria. Phone: 43-1-40490-79502. Fax: 43-1-40490-9795. E-mail: christian.mandl{at}meduniwien.ac.at.

Journal of Virology, April 2006, p. 4099-4113, Vol. 80, No. 8
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.8.4099-4113.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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