Abstract

Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks taking a considerable toll in human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic, and emerging RNA virus infections in humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work, we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies and a decrease of specific infectivity, hallmarks of lethal mutagenesis.

Highlights

  • Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks taking a considerable toll in human deaths in many African countries, for which no effective treatment is available

  • The aim of this work was to determine whether favipiravir induces lethal mutagenesis upon RVFV infection in cell culture

  • As expected from the previous results (Fig. 1), favipiravir concentrations over 5 ␮M significantly reduced the yield of either the parental or the serially passaged RVFV 56/74 not treated with the drug, while for the virus selected after 8 passages in the presence of 40 ␮M favipiravir, a 50% reduction in aac.asm.org 2

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Summary

Introduction

Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks taking a considerable toll in human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T705) has demonstrated great potential for the treatment of several seasonal, chronic, and emerging RNA virus infections in humans, suggesting applicability to control some viral outbreaks. Mechanism of action of favipiravir against RVFV in cell culture is due, at least in part, to the accumulation of mutations in the viral genome that leads to a progressive decrease in viable viral progeny This conclusion is based on a significant increase of mutation frequency measured in a 1,060-bp fragment from the Gc (glycoprotein C)-coding region and a concomitant decrease of specific infectivity associated with virus extinction, supporting the use of favipiravir for the control of emerging RVFV infections in humans

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