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Journal of Virology, September 2004, p. 9798-9806, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.9798-9806.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

NSs Protein of Rift Valley Fever Virus Blocks Interferon Production by Inhibiting Host Gene Transcription

Agnès Billecocq,1,{dagger} Martin Spiegel,2,{dagger} Pierre Vialat,1 Alain Kohl,1,{ddagger} Friedemann Weber,2 Michèle Bouloy,1* and Otto Haller2*

Unité de génétique moléculaire des Bunyaviridés, Institut Pasteur, Paris, France,1 Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Freiburg, Germany2

Received 9 March 2004/ Accepted 7 May 2004

Rift Valley fever virus (RVFV) is an important cause of epizootics and epidemics in Africa and a potential agent of bioterrorism. A better understanding of the factors that govern RVFV virulence and pathogenicity is required, given the urgent need for antiviral therapies and safe vaccines. We have previously shown that RVFV strains with mutations in the NSs gene are excellent inducers of {alpha}/ß interferon (IFN-{alpha}/ß) and are highly attenuated in mice. Here, we demonstrate that NSs is sufficient to block IFN-ß gene expression at the transcriptional level. In cells transiently expressing NSs, IFN-ß transcripts were not inducible by viral infection or by transfection of poly(I:C). NSs with anti-IFN activity accumulated in the nucleus. In contrast, mutant forms of NSs that had lost their IFN-inhibiting activity remained in the cytoplasm, indicating that nuclear localization plays a role. IFN synthesis is regulated by specific transcription factors, including interferon regulatory factor (IRF-3), NF-{kappa}B, and AP-1. In the presence of NSs, IRF-3 was still activated and moved to the nucleus. Likewise, NF-{kappa}B and AP-1 were activated normally, as shown in electrophoretic mobility shift assays. Moreover, NSs was found to inhibit transcriptional activity of a constitutive promoter, in agreement with recent findings showing that NSs targets the basal cellular transcription factor TFIIH. The present results suggest that NSs, unlike other viral IFN antagonists, does not inhibit IFN-specific transcription factors but blocks IFN gene expression at a subsequent step.

* Corresponding author. Mailing address for Otto Haller: Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, D79008 Freiburg, Germany. Phone: 49-761-2036534. Fax: 49-761-2036626. E-mail: otto.haller{at}uniklinik-freiburg.de. Mailing address for Michèle Bouloy: Institut Pasteur, 25 rue du Dr. Roux, F-75724 Paris Cedex 15, France. Phone: 33 1 40 61 31 57. Fax: 33 1 40 61 31 51. E-mail: mbouloy{at}pasteur.fr.

{dagger} A.B. and M.S. contributed equally to this work.

{ddagger} Present address: Division of Virology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland.

Journal of Virology, September 2004, p. 9798-9806, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.9798-9806.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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