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Maporal Virus as a Surrogate for Pathogenic New World Hantaviruses and its Inhibition by Favipiravir

Background: Pathogenic hantaviruses geographically distributed in the Old World cause haemorrhagic fever with renal syndrome (HFRS), whereas New World hantaviruses are the aetiological agents of hantavirus cardiopulmonary syndrome (HCPS). Ribavirin, a drug associated with toxicities, is presently indicated for treatment of HFRS, whereas treatment of the more frequently lethal HCPS is limited to supportive care. Because of the need for safe and effective antivirals to treat severe hantaviral infections, we evaluated favipiravir (T-705) against Dobrava and Maporal viruses as representative Old World and New World hantaviruses, respectively. Dobrava virus causes HFRS in Europe. Maporal virus (MPRLV), recently isolated from western Venezuela, is phylogenetically similar to Andes virus, the principal cause of HCPS in Argentina. Methods: Hantavirus replication in the presence of various inhibitors was measured by focus-forming unit assays and quantitative reverse transcriptase PCR. Phylogenetic relationships were assessed by the neighbour-joining and bootstrap consensus methods. Results: Here, we show that infection of Vero E6 cells with MPRLV is dependent on β3 integrins, similar to that reported for pathogenic hantaviruses. Furthermore, by analysis of molecular determinants associated with the G1 glycoprotein cytoplasmic tail, we show the close genetic proximity of MPRLV to other HCPS-causing hantaviruses in these regions predictive of pathogenicity. We also demonstrate anti-hantavirus activity by favipiravir with inhibitory concentrations ranging from 65 to 93 μM and selectivity indices >50. Conclusions: Our data suggest that MPRLV may serve as a safer alternative to modelling infection caused by the highly lethal Andes virus and that hantaviruses are sensitive to the effects of favipiravir in cell culture.