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Open Access Research

Inhibition of Hazara nairovirus replication by small interfering RNAs and their combination with ribavirin

Olivier Flusin1*, Solenne Vigne13, Christophe N Peyrefitte1, Michèle Bouloy2, Jean-Marc Crance1 and Frédéric Iseni1

Author Affiliations

1 Unité de virologie, Institut de Recherche Biomédicale des Armées (IRBA), 24 avenue des Maquis du Grésivaudan 38702 La Tronche, France

2 Unité de Génétique Moléculaire des Bunyavirus, Institut Pasteur, 25 rue du docteur Roux 75724 Paris cedex 15, France

3 Department of Pathology and Immunology, Centre Médical Universitaire, 1 rue Michel Servet 1211 Geneva 4, Switzerland

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Virology Journal 2011, 8:249  doi:10.1186/1743-422X-8-249

Published: 21 May 2011

Abstract

Background

The genus Nairovirus in the family Bunyaviridae contains 34 tick-borne viruses classified into seven serogroups. Hazara virus (HAZV) belongs to the Crimean-Congo hemorrhagic fever (CCHF) serogroup that also includes CCHF virus (CCHFV) a major pathogen for humans. HAZV is an interesting model to study CCHFV due to a close serological and phylogenetical relationship and a classification which allows handling in a BSL2 laboratory. Nairoviruses are characterized by a tripartite negative-sense single stranded RNA genome (named L, M and S segments) that encode the RNA polymerase, the Gn-Gc glycoproteins and the nucleoprotein (NP), respectively. Currently, there are neither vaccines nor effective therapies for the treatment of any bunyavirus infection in humans. In this study we report, for the first time, the use of RNA interference (RNAi) as an approach to inhibit nairovirus replication.

Results

Chemically synthesized siRNAs were designed to target the mRNA produced by the three genomic segments. We first demonstrated that the siRNAs targeting the NP mRNA displayed a stronger antiviral effect than those complementary to the L and M transcripts in A549 cells. We further characterized the two most efficient siRNAs showing, that the induced inhibition is specific and associated with a decrease in NP synthesis during HAZV infection. Furthermore, both siRNAs depicted an antiviral activity when used before and after HAZV infection. We next showed that HAZV was sensitive to ribavirin which is also known to inhibit CCHFV. Finally, we demonstrated the additive or synergistic antiviral effect of siRNAs used in combination with ribavirin.

Conclusions

Our study highlights the interest of using RNAi (alone or in combination with ribavirin) to treat nairovirus infection. This approach has to be considered for the development of future antiviral compounds targeting CCHFV, the most pathogenic nairovirus.