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Journal of Virology, August 2003, p. 8426-8439, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8426-8439.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Role of Alpha/Beta Interferons in the Attenuation and Immunogenicity of Recombinant Bovine Respiratory Syncytial Viruses Lacking NS Proteins

Jean-Francois Valarcher,1,2* Julie Furze,1 Sara Wyld,1 Roy Cook,1 Karl-Klaus Conzelmann,3 and Geraldine Taylor1

Institute for Animal Health, Compton, Newbury, Berkshire RG20 7NN, United Kingdom,1 UMR INRA-ENVT 1225, ENVT, 31076 Toulouse cedex 3, France,2 Max von Pettenkofer Institute & Gene Center, Ludwig-Maximillians-University, D-81377 Munich, Germany3

Received 27 February 2003/ Accepted 6 May 2003

Alpha/beta interferons (IFN-{alpha}/ß) are not only a powerful first line of defense against pathogens but also have potent immunomodulatory activities. Many viruses have developed mechanisms of subverting the IFN system to enhance their virulence. Previous studies have demonstrated that the nonstructural (NS) genes of bovine respiratory syncytial virus (BRSV) counteract the antiviral effects of IFN-{alpha}/ß. Here we demonstrate that, in contrast to wild-type BRSVs, recombinant BRSVs (rBRSVs) lacking the NS proteins, and those lacking NS2 in particular, are strong inducers of IFN-{alpha}/ß in bovine nasal fibroblasts and bronchoalveolar macrophages. Furthermore, whereas the NS deletion mutants replicated to wild-type rBRSV levels in cells lacking a functional IFN-{alpha}/ß system, their replication was severely attenuated in IFN-competent cells and in young calves. These results suggest that the NS proteins block the induction of IFN-{alpha}/ß gene expression and thereby increase the virulence of BRSV. Despite their poor replication in the respiratory tract of young calves, prior infection with virus lacking either the NS1 or the NS2 protein induced serum antibodies and protection against challenge with virulent BRSV. The greater level of protection induced by the NS2, than by the NS1, deletion mutant, was associated with higher BRSV-specific antibody titers and greater priming of BRSV-specific, IFN-{gamma}-producing CD4+ T cells. Since there were no detectable differences in the ability of these mutants to replicate in the bovine respiratory tract, the greater immunogenicity of the NS2 deletion mutant may be associated with the greater ability of this virus to induce IFN-{alpha}/ß.

* Corresponding author. Mailing address: Institute for Animal Health, Compton, Newbury, Berkshire RG20 7NN, United Kingdom. Phone: 44 1635 577290. Fax: 44 1635 577263. E-mail: jean-francois.valarcher{at}bbsrc.ac.uk.

Journal of Virology, August 2003, p. 8426-8439, Vol. 77, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.15.8426-8439.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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