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

Abstract

Background Pathogenic hantaviruses geographically distributed in the Old World cause hemorrhagic fever with renal syndrome (HFRS), whereas New World hantaviruses are the etiological agents of hantavirus cardiopulmonary syndrome (HCPS). Ribavirin, a drug associated with toxicities, is presently indicated for treatment of HFRS, while 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 very similar phylogenetically to Andes virus (ANDV), the principal cause of HCPS in Argentina. Presently, there is no evidence that MPRLV can cause disease in humans. Methods and Results Here, we show that infection of Vero E6 cells with MPRLV is dependent on β3 integrins, similar to that reported for pathogenic hantaviruses. Further, by analysis of genetic 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. Using focus-forming unit assays and measuring viral RNA by quantitative RT-PCR, we demonstrate anti-hantavirus activity by favipiravir with inhibitory concentrations ranging from 65 - 93 μM and selectivity indices > 50. Conclusions Our data suggest that MPRLV may serve as a safer alternative to modeling infection caused by the highly lethal ANDV and that hantaviruses are sensitive to the effects of favipiravir in cell culture.

The Syrian hamster model of hantavirus pulmonary syndrome

“…The parallels between the human trials and the recent studies in hamsters further validate the use of the model for evaluating future therapies. Although no other antiviral agents have been tested against HPS in either humans or hamsters, some, including T-705, have shown promise in vitro and should be evaluated using in vivo models (Buys et al, 2011). …”

Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment

“…Additionally, the antiviral activity of T-705 in vitro against several other related bunyaviruses (several hantaviruses, La Crosse virus, and Punta Toro and sandfly fever phleboviruses) have been reported (Buys et al, 2011; Gowen et al, 2007; Safronetz et al, 2013). Punta Toro virus (PTV), a more accessible and less biohazardous agent (biosafety level 2; BSL-2) belonging to the same genus as RVFV, has been used to model severe RVFV infection in different animal models (Anderson et al, 1990; Fisher et al, 2003; Pifat and Smith, 1987).…”

Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses In Vitro and against Human Metapneumovirus in Hamsters

“…T-705 is presently in clinical development as an influenza virus inhibitor in Japan (new drug application filed) and the United States (phase 3 clinical trial) (18). Antiviral activity has been demonstrated against a broad range of negative-strand RNA viruses, such as members of the Picorna-, Arena-, Bunya-, and Filoviridae (25)(26)(27)(28)(29)(30), and positive-strand RNA viruses, such as the Noro-and Flavivirus genera (31,32). Here we evaluated the activity of T-705 against a broad range of paramyxoviruses in vitro and against HMPV in hamsters.…”