Abstract
BackgroundLethal mutagenesis is a transition towards virus extinction mediated by enhanced mutation rates during viral genome replication, and it is currently under investigation as a potential new antiviral strategy. Viral load and virus fitness are known to influence virus extinction. Here we examine the effect or the multiplicity of infection (MOI) on progeny production of several RNA viruses under enhanced mutagenesis.ResultsThe effect of the mutagenic base analogue 5-fluorouracil (FU) on the replication of the arenavirus lymphocytic choriomeningitis virus (LCMV) can result either in inhibition of progeny production and virus extinction in infections carried out at low multiplicity of infection (MOI), or in a moderate titer decrease without extinction at high MOI. The effect of the MOI is similar for LCMV and vesicular stomatitis virus (VSV), but minimal or absent for the picornaviruses foot-and-mouth disease virus (FMDV) and encephalomyocarditis virus (EMCV). The increase in mutation frequency and Shannon entropy (mutant spectrum complexity) as a result of virus passage in the presence of FU was more accentuated at low MOI for LCMV and VSV, and at high MOI for FMDV and EMCV. We present an extension of the lethal defection model that agrees with the experimental results.Conclusions(i) Low infecting load favoured the extinction of negative strand viruses, LCMV or VSV, with an increase of mutant spectrum complexity. (ii) This behaviour is not observed in RNA positive strand viruses, FMDV or EMCV. (iii) The accumulation of defector genomes may underlie the MOI-dependent behaviour. (iv) LCMV coinfections are allowed but superinfection is strongly restricted in BHK-21 cells. (v) The dissimilar effects of the MOI on the efficiency of mutagenic-based extinction of different RNA viruses can have implications for the design of antiviral protocols based on lethal mutagenesis, presently under development.
Highlights
RNA viruses display high mutation rates and frequencies that lead to the generation of dynamic mutant spectra termed viral quasispecies [1,2,3,4,5,6,7,8]
We have examined the effect of the initial viral dose on Lymphocytic choriomeningitis virus (LCMV) extinction, and found that following infection at low multiplicity of infection (MOI), FU inhibited production of infectious progeny of LCMV, as well as of the rhabdovirus vesicular stomatitis virus (VSV), to a much larger extent than foot-and-mouth disease virus (FMDV) or encephalomyocarditis virus (EMCV)
The effect of MOI on progeny production of LCMV RNA was less pronounced than the effect on infectivity, and the differences between RNA progeny at different MOIs did not reach statistical significance (Figs. 2B and 2C)
Summary
RNA viruses display high mutation rates and frequencies that lead to the generation of dynamic mutant spectra termed viral quasispecies [1,2,3,4,5,6,7,8]. A new antiviral strategy termed lethal mutagenesis aims at increasing the viral mutation rate beyond a biologically tolerable threshold, resulting in reduced viral fitness and, eventually, virus extinction [9,10,11,12,13,14]. Lethal mutagenesis is a transition towards virus extinction mediated by enhanced mutation rates during viral genome replication, and it is currently under investigation as a potential new antiviral strategy. We examine the effect or the multiplicity of infection (MOI) on progeny production of several RNA viruses under enhanced mutagenesis
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