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

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.

• Authors: Olivier Flusin, Solenne Vigne, Christophe N Peyrefitte, Michèle Bouloy, Jean-Marc Crance, Frédéric Iseni
• Journal: Virology journal (Virol J) Vol. 8 Pg. 249 (May 21 2011) ISSN: 1743-422X [Electronic] England
• PMID: 21600011 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Biological Products
• RNA, Small Interfering
• Ribavirin

Topics

• Animals
• Antiviral Agents (pharmacology)
• Biological Products (pharmacology)
• Cell Line
• Chlorocebus aethiops
• Drug Synergism
• Humans
• Microbial Sensitivity Tests
• Nairovirus (drug effects, physiology)
• RNA, Small Interfering (pharmacology)
• Ribavirin (pharmacology)
• Virus Replication (drug effects)