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Journal of Virology, August 2004, p. 8812-8823, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8812-8823.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Determinants of Virulence of Classical Swine Fever Virus Strain Brescia

H. G. P. van Gennip,* A. C. Vlot,{dagger} M. M. Hulst, A. J. de Smit,{ddagger} and R. J. M. Moormann

Animal Sciences Group, Wageningen University and Research Centre, 8200 AM Lelystad, The Netherlands1

Received 23 January 2004/ Accepted 22 April 2004

Two related classical swine fever virus (CSFV) strain Brescia clones were isolated from blood samples from an infected pig. Virus C1.1.1 is a cell-adapted avirulent variant, whereas CoBrB is a virulent variant. Sequence analysis revealed 29 nucleic acid mutations in C1.1.1, resulting in 9 amino acid substitutions compared to the sequence of CoBrB 476R. Using reverse genetics, parts of the genomes of these viruses, which contain differences that lead to amino acid changes, were exchanged. Animal experiments with chimeric viruses derived from C1.1.1 and CoBrB 476R showed that a combination of amino acid changes in the structural and nonstructural regions reduced the virulence of CSFV in pigs. Moreover, the presence of a Leu at position 710 in structural envelope protein E2 seemed to be an important factor in the virulence of the virus. Changing the Leu at position 710 in the CoBrB 476S variant into a His residue did not affect virulence. However, the 710His in the C1.1.1/CoBrB virus, together with adaptive mutations 276R, 476R, and 477I in Erns, resulted in reduced virulence in pigs. These results indicated that mutations in Erns and E2 alone do not determine virulence in pigs. The results of in vitro experiments suggested that a high affinity for heparan sulfate of C1.1.1 Erns may reduce the spread of the C1.1.1/CoBrB virus in pigs and together with the altered surface structure of E2 caused by the 710L->H mutation may result in a less efficient infection of specific target cells in pigs. Both these features contributed to the attenuation of the C1.1.1/CoBrB virus in vivo.

* Corresponding author. Mailing address: Department of Notifiable and Exotic Viral Diseases, Central Institute of Animal Disease Control (CIDC-Lelystad), Wageningen UR, P.O. Box 2004, 8203 AA Lelystad, The Netherlands. Phone: 31 320 238238. Fax: 31 320 238668. E-mail: RENE.VANGENNIP{at}WUR.NL.

{dagger} Present address: Boyce Thompson Institute for Plant Research, Ithaca, NY.

{ddagger} Present address: Intervet International B.V., Boxmeer, The Netherlands.

Journal of Virology, August 2004, p. 8812-8823, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8812-8823.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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