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Journal of Virology, February 2001, p. 1371-1377, Vol. 75, No. 3
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.3.1371-1377.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Genetic Evidence for an Interferon-Antagonistic
Function of Rift Valley Fever Virus Nonstructural Protein NSs
Michèle
Bouloy,1
Christian
Janzen,2,
Pierre
Vialat,1
Huot
Khun,3
Jovan
Pavlovic,4
Michel
Huerre,3 and
Otto
Haller2,*
Groupe des
Bunyaviridés1 and Unité
d'Histopathologie,3 Institut Pasteur, F-75724
Paris Cedex, France; Institute of Medical Virology, University
of Zürich, CH-8028 Zürich,
Switzerland4; and Abteilung Virologie,
Institut für Medizinische Mikrobiologie und Hygiene,
Universität Freiburg, D-79008 Freiburg,
Germany2
Received 21 August 2000/Accepted 3 November 2000
Rift Valley fever virus (RVFV), a phlebovirus of the
family Bunyaviridae, is a major public health threat in
Egypt and sub-Saharan Africa. The viral and host cellular factors that
contribute to RVFV virulence and pathogenicity are still poorly
understood. All pathogenic RVFV strains direct the synthesis of a
nonstructural phosphoprotein (NSs) that is encoded by the smallest (S)
segment of the tripartite genome and has an undefined accessory
function. In this report, we show that MP12 and clone 13, two
attenuated RVFV strains with mutations in the NSs gene, were highly
virulent in IFNAR
/
mice lacking the alpha/beta
interferon (IFN-
/
) receptor but remained attenuated in IFN-
receptor-deficient mice. Both attenuated strains proved to be excellent
inducers of early IFN-
/
production. In contrast, the virulent
strain ZH548 failed to induce detectable amounts of IFN-
/
and
replicated extensively in both IFN-competent and IFN-deficient mice.
Clone 13 has a defective NSs gene with a large in-frame deletion. This
defect in the NSs gene results in expression of a truncated protein
which is rapidly degraded. To investigate whether the presence of the
wild-type NSs gene correlated with inhibition of IFN-
/
production, we infected susceptible IFNAR
/
mice with S
gene reassortant viruses. When the S segment of ZH548 was replaced by
that of clone 13, the resulting reassortants became strong IFN
inducers. When the defective S segment of clone 13 was exchanged with
the wild-type S segment of ZH548, the reassortant virus lost the
capacity to stimulate IFN-
/
production. These results demonstrate
that the ability of RVFV to inhibit IFN-
/
production correlates
with viral virulence and suggest that the accessory protein NSs is an
IFN antagonist.
*
Corresponding author. Mailing address: Abteilung
Virologie, Institut für Medizinische Mikrobiologie und Hygiene,
Universität Freiburg, D-79008 Freiburg, Germany. Phone:
49-761-2036534. Fax: 49-761-2036626. E-mail:
HALLER{at}UKL.UNI-FREIBURG.DE.

Present address: The Rockefeller University, New York, NY
10021.
Journal of Virology, February 2001, p. 1371-1377, Vol. 75, No. 3
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.3.1371-1377.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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