Abstract
Frequent mumps outbreaks in vaccinated populations and the occurrence of neurological complications (e.g., aseptic meningitis or encephalitis) in patients with mumps indicate the need for the development of more efficient vaccines as well as specific antiviral therapies. RNA viruses are genetically highly heterogeneous populations that exist on the edge of an error threshold, such that additional increases in mutational burden can lead to extinction of the virus population. Deliberate modulation of their natural mutation rate is being exploited as an antiviral strategy and a possibility for rational vaccine design. The aim of this study was to examine the ability of ribavirin, a broad-spectrum antiviral agent, to introduce mutations in the mumps virus (MuV) genome and to investigate if resistance develops during long-term in vitro exposure to ribavirin. An increase in MuV population heterogeneity in the presence of ribavirin has been observed after one passage in cell culture, as well as a bias toward C-to-U and G-to-A transitions, which have previously been defined as ribavirin-related. At higher ribavirin concentration, MuV loses its infectivity during serial passaging and does not recover. At low ribavirin concentration, serial passaging leads to a more significant increase in population diversity and a stronger bias towards ribavirin-related transitions, independently of viral strain or cell culture. In these conditions, the virus retains its initial growth capacity, without development of resistance at a whole-virus population level.
Highlights
Mumps orthorubulavirus (MuV) is a nonsegmented, negative-sense (NNS) RNA virus, belonging to the genus Orthorubulavirus in the family Paramyxoviridae
To address the potential mutagenic action of RBV against MuV, we have chosen two different viruses: MuVi-C, a plaque-purified variant obtained from the L-Zagreb vaccine, and ZgA/Cro69, derived from the wild-type virus by continuous passages in the cell culture
As the antiviral activity of RBV is observed through a decrease in viral titre following in vitro infection, we paired chosen MuV strains with substrates where they grow to high titres (Vero cells for MuVi-C; A549 cells for ZgA/Cro69)
Summary
Mumps orthorubulavirus (MuV) is a nonsegmented, negative-sense (NNS) RNA virus, belonging to the genus Orthorubulavirus in the family Paramyxoviridae. It causes a respiratory infection, which, in most cases, naturally passes within two weeks. Due to the highly neurotropic nature of this virus, aseptic meningitis and encephalitis arise in 1–10%. 0.1% of mumps infections, respectively [1]. An approved antiviral treatment, which would be extremely beneficial in these cases, does not exist. Live-attenuated vaccines are used worldwide and have greatly helped to decrease the incidence rate of mumps. Epidemics frequently occur due to genetic differences between vaccine strains and currently circulating viral strains, as well as primary or secondary vaccine failure (reviewed in [2])
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