July 25, 2022
On July 11, 2022, a paper on the potential and action mechanism of favipiravir as an antiviral against Junin virus by a research group of Dr. Vahid Rajabali Zadeh and Prof. Jiro Yasuda, Department of Emerging Infectious Diseases, National Research Center for the Control and Prevention of Infectious Diseases/Institute of Tropical Medicine, was published online in the journal "PLOS Pathogens".
Favipiravir is a nucleoside analogue that inhibits the replication and transcription of a broad spectrum of RNA viruses, including pathogenic arenaviruses. In this study, we isolated a favipiravir-resistant mutant of Junin virus (JUNV), which is the causative agent of Argentine hemorrhagic fever, and analyzed the antiviral mechanism of favipiravir against JUNV. Two amino acid substitutions, N462D in the RNA-dependent RNA polymerase (RdRp) and A168T in the glycoprotein precursor GPC, were identified in the mutant. GPC-A168T substitution enhanced the efficiency of JUNV internalization, which explains the robust replication kinetics of the mutant in the virus growth analysis. Although RdRp-N462D substitution did not affect polymerase activity levels in a minigenome system, comparisons of RdRp error frequencies showed that the virus with RdRp-D462 possessed a significantly higher fidelity. Our next generation sequence (NGS) analysis showed a gradual accumulation of both mutations as we passaged the virus in presence of favipiravir. We also provided experimental evidence for the first time that favipiravir inhibited JUNV through the accumulation of transition mutations, confirming its role as a purine analogue against arenaviruses. Moreover, we showed that treatment with a combination of favipiravir and either ribavirin or remdesivir inhibited JUNV replication in a synergistic manner, blocking the generation of the drug-resistant mutant. Our findings provide new insights for the clinical management and treatment of Argentine hemorrhagic fever.
When the BSL-4 facility would operate at Nagasaki University, we expect to be able to further evaluate the effectiveness of the treatment through animal experiments and other means.
For the details of this research, see “Potential and action mechanism of favipiravir as an antiviral against Junin virus” Zadeh VR, Afowowe TO, Abe H, Urata S, Yasuda J, PLoS Pathogens, 18(7): e1010689, 2022.
This release is also available in Japanese.