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Journal of Virology, July 2005, p. 8602-8613, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8602-8613.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Attenuation of Recombinant Yellow Fever 17D Viruses Expressing Foreign Protein Epitopes at the Surface

Myrna C. Bonaldo,1 Richard C. Garratt,2 Renato S. Marchevsky,3 Evandro S. F. Coutinho,4 Alfredo V. Jabor,1 Luís F. C. Almeida,3 Anna M. Y. Yamamura,3 Adriana S. Duarte,1 Prisciliana J. Oliveira,1 Jackeline O. P. Lizeu,1 Luiz A. B. Camacho,4 Marcos S. Freire,3 and Ricardo Galler1*

Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Departamento de Bioquimica e Biologia Molecular,1 Fundação Oswaldo Cruz, Instituto de Tecnologia em Imunobiológicos, Departamento de Controle de Qualidade,3 Escola Nacional de Saúde Pública, Rio de Janeiro,4 Universidade de São Paulo, Instituto de Física de São Carlos, São Carlos, Brazil2

Received 26 November 2004/ Accepted 13 March 2005

The yellow fever (YF) 17D vaccine is a live attenuated virus. Three-dimensional (3D) homology modeling of the E protein structure from YF 17D virus and its comparison with that from tick-borne encephalitis virus revealed that it is possible to accommodate inserts of different sizes and amino acid compositions in the flavivirus E protein fg loop. This is consistent with the 3D structures of both the dimeric and trimeric forms in which the fg loop lies exposed to solvents. We demonstrate here that YF 17D viruses bearing foreign humoral (17D/8) and T-cell (17D/13) epitopes, which vary in sequence and length, displayed growth restriction. It is hypothesized that interference with the dimer-trimer transition and with the formation of a ring of such trimers in order to allow fusion compromises the capability of the E protein to induce fusion of viral and endosomal membranes, and a slower rate of fusion may delay the extent of virus production. This would account for the lower levels of replication in cultured cells and of viremia in monkeys, as well as for the more attenuated phenotype of the recombinant viruses in monkeys. Testing of both recombinant viruses (17D/8 and 17D/13) for monkey neurovirulence also suggests that insertion at the 17D E protein fg loop does not compromise the attenuated phenotype of YF 17D virus, further confirming the potential use of this site for the development of new live attenuated 17D virus-based vaccines.

* Corresponding author. Mailing address: Departamento de Bioquimica e Biologia Molecular, Fundação Oswaldo Cruz., Avenida Brasil 4365, Manguinhos, Rio de Janeiro, RJ, Brazil, 21040-900. Phone: 55 21 3865 8112. Fax: 55 21 2590 3495. E-mail: rgaller{at}ioc.fiocruz.br.

Journal of Virology, July 2005, p. 8602-8613, Vol. 79, No. 13
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.13.8602-8613.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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