Abstract
Flaviviruses constitute an increasing source of public health concern, with growing numbers of pathogens causing disease and geographic spread to temperate climates. Despite a large body of evidence supporting mutagenesis as a conceivable antiviral strategy, there are currently no data on the sensitivity to increased mutagenesis for Zika virus (ZIKV) and Usutu virus (USUV), two emerging flaviviral threats. In this study, we demonstrate that both viruses are sensitive to three ribonucleosides, favipiravir, ribavirin, and 5-fluorouracil, that have shown mutagenic activity against other RNA viruses while remaining unaffected by a mutagenic deoxyribonucleoside. Serial cell culture passages of ZIKV in the presence of these compounds resulted in the rapid extinction of infectivity, suggesting elevated sensitivity to mutagenesis. USUV extinction was achieved when a 10-fold dilution was applied between every passage, but not in experiments involving undiluted virus, indicating an overall lower susceptibility than ZIKV. Although the two viruses are inhibited by the same three drugs, ZIKV is relatively more susceptive to serial passage in the presence of purine analogues (favipiravir and ribavirin), while USUV replication is suppressed more efficiently by 5-fluorouracil. These differences in sensitivity typically correlate with the increases in the mutation frequencies observed in each nucleoside treatment. These results are relevant to the development of efficient therapies based on lethal mutagenesis and support the rational selection of different mutagenic nucleosides for each pathogen. We will discuss the implications of these results to the fidelity of flavivirus replication and the design of antiviral therapies based on lethal mutagenesis.
Highlights
Human disease caused by flaviviruses represents a growing source of global health concern, with elevated numbers of deaths and cases of severe disease [1, 2]
To investigate whether Zika virus (ZIKV) replication could be affected by increased mutagenesis, we tested four different compounds known to be mutagenic for diverse viruses, 5-fluorouracil, ribavirin, favipiravir, and decitabine [25, 32, 35, 37,38,39]
Its antiviral activity has been associated with lethal mutagenesis, and it is possibly related to the incorporation of the phosphorylated deoxyribonucleoside derivative into viral cDNA during reverse transcription [39, 67]
Summary
Human disease caused by flaviviruses represents a growing source of global health concern, with elevated numbers of deaths and cases of severe disease [1, 2]. The rationale for antiviral therapies based on mutagenesis stems from theoretical studies by Eigen and colleagues [27, 28] These investigations led to the proposal that the elevated error frequencies during RNA virus replication are in the proximity of a maximum tolerated value for viability, namely, the error threshold [28,29,30]. It remains unclear whether two different related pathogens can have different responses to the treatment with the same mutagenic compounds or whether they show distinct sensitivity to them This information could be relevant in the design of broad-spectrum antiviral therapies against the flaviviruses based on lethal mutagenesis
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