Remdesivir inhibits the polymerases of the novel filoviruses Lloviu and Bombali virus.

In recent years, a number of novel filoviruses (e.g. Lloviu virus (LLOV) and Bombali virus (BOMV)) have been discovered. While antibody-based therapeutics have recently been approved for treatment of infections with the filovirus Ebola virus (EBOV), no treatment options for novel filoviruses currently exist. Further, the development of antivirals against them is complicated by the fact that only sequence information, but no actual virus isolates, are available. To address this issue, we developed a reverse genetics-based minigenome system for BOMV, which allows us to assess the activity of the BOMV polymerase. Together with similar systems that we have developed for other filoviruses in the past (i.e. LLOV and Reston virus (RESTV)), we then assessed the efficiency of remdesivir, a known inhibitor of the EBOV polymerase that has recently been tested in a clinical trial for efficacy against Ebola disease. We show that remdesivir is indeed also active against the polymerases of BOMV, LLOV, and RESTV, with comparable IC50 values to its activity against EBOV. This suggests that treatment with remdesivir might represent a viable option in case of infections with novel filoviruses.

Differences in Viral RNA Synthesis but Not Budding or Entry Contribute to the In Vitro Attenuation of Reston Virus Compared to Ebola Virus.

Most filoviruses cause severe disease in humans. For example, Ebola virus (EBOV) is responsible for the two most extensive outbreaks of filovirus disease to date, with case fatality rates of 66% and 40%, respectively. In contrast, Reston virus (RESTV) is apparently apathogenic in humans, and while transmission of RESTV from domestic pigs to people results in seroconversion, no signs of disease have been reported in such cases. The determinants leading to these differences in pathogenicity are not well understood, but such information is needed in order to better evaluate the risks posed by the repeated spillover of RESTV into the human population and to perform risk assessments for newly emerging filoviruses with unknown pathogenic potential. Interestingly, RESTV and EBOV already show marked differences in their growth in vitro, with RESTV growing slower and reaching lower end titers. In order to understand the basis for this in vitro attenuation of RESTV, we used various life cycle modeling systems mimicking different aspects of the virus life cycle. Our results showed that viral RNA synthesis was markedly slower when using the ribonucleoprotein (RNP) components from RESTV, rather than those for EBOV. In contrast, the kinetics of budding and entry were indistinguishable between these two viruses. These data contribute to our understanding of the molecular basis for filovirus pathogenicity by showing that it is primarily differences in the robustness of RNA synthesis by the viral RNP complex that are responsible for the impaired growth of RESTV in tissue culture.