Mutagenesis-Mediated Virus Extinction: Virus-Dependent Effect of Viral Load on Sensitivity to Lethal Defection

Moreno, Hector; Tejero, Héctor; Torre, Juan Carlos de la; Domingo, Esteban; Martı́n, Verónica

doi:10.1371/journal.pone.0032550

Cited by 25 publications

(23 citation statements)

References 88 publications

(157 reference statements)

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“…These features are a hallmark of virus extinction by lethal mutagenesis [reviewed in [114], [115]]. Extinction by Rib occurred with a 5-fold to 23-fold decrease of specific infectivity, as quantified by infectivity and viral RNA in samples of the cell culture supernatants (Fig.…”

Section: Resultsmentioning

confidence: 99%

Extinction of Hepatitis C Virus by Ribavirin in Hepatoma Cells Involves Lethal Mutagenesis

et al. 2013

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Lethal mutagenesis, or virus extinction produced by enhanced mutation rates, is under investigation as an antiviral strategy that aims at counteracting the adaptive capacity of viral quasispecies, and avoiding selection of antiviral-escape mutants. To explore lethal mutagenesis of hepatitis C virus (HCV), it is important to establish whether ribavirin, the purine nucleoside analogue used in anti-HCV therapy, acts as a mutagenic agent during virus replication in cell culture. Here we report the effect of ribavirin during serial passages of HCV in human hepatoma Huh-7.5 cells, regarding viral progeny production and complexity of mutant spectra. Ribavirin produced an increase of mutant spectrum complexity and of the transition types associated with ribavirin mutagenesis, resulting in HCV extinction. Ribavirin-mediated depletion of intracellular GTP was not the major contributory factor to mutagenesis since mycophenolic acid evoked a similar decrease in GTP without an increase in mutant spectrum complexity. The intracellular concentration of the other nucleoside-triphosphates was elevated as a result of ribavirin treatment. Mycophenolic acid extinguished HCV without an intervening mutagenic activity. Ribavirin-mediated, but not mycophenolic acid-mediated, extinction of HCV occurred via a decrease of specific infectivity, a feature typical of lethal mutagenesis. We discuss some possibilities to explain disparate results on ribavirin mutagenesis of HCV.

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Section: Resultsmentioning

confidence: 99%

Extinction of Hepatitis C Virus by Ribavirin in Hepatoma Cells Involves Lethal Mutagenesis

et al. 2013

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“…In Moreno et al (2012), a computational model based on interference-complementation interactions was developed to find out to what extent lethal defection can explain the effect of the initial MOI on lethal mutagenesis in certain viruses. Besides considering various phenotypic traits, the model was characterised by its consideration of a partial trans interaction and for coupling, in a nested way, the intra-and extracellular dynamics of RNA virus infections.…”

Section: Interference Complementation and Lethal Defectionmentioning

confidence: 99%

Theories of Lethal Mutagenesis: From Error Catastrophe to Lethal Defection

Tejero

Montero

Nuño

2015

Current Topics in Microbiology and Immunology

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RNA viruses get extinct in a process called lethal mutagenesis when subjected to an increase in their mutation rate, for instance, by the action of mutagenic drugs. Several approaches have been proposed to understand this phenomenon. The extinction of RNA viruses by increased mutational pressure was inspired by the concept of the error threshold. The now classic quasispecies model predicts the existence of a limit to the mutation rate beyond which the genetic information of the wild type could not be efficiently transmitted to the next generation. This limit was called the error threshold, and for mutation rates larger than this threshold, the quasispecies was said to enter into error catastrophe. This transition has been assumed to foster the extinction of the whole population. Alternative explanations of lethal mutagenesis have been proposed recently. In the first place, a distinction is made between the error threshold and the extinction threshold, the mutation rate beyond which a population gets extinct. Extinction is explained from the effect the mutation rate has, throughout the mutational load, on the reproductive ability of the whole population. Secondly, lethal defection takes also into account the effect of interactions within mutant spectra, which have been shown to be determinant for the understanding the extinction of RNA virus due to an augmented mutational pressure. Nonetheless, some relevant issues concerning lethal mutagenesis are not completely understood yet, as so survival of the flattest, i.e. the development of resistance to lethal mutagenesis by evolving towards mutationally more robust regions of sequence space, or sublethal mutagenesis, i.e., the increase of the mutation rate below the extinction threshold which may boost the adaptability of RNA virus, increasing their ability to develop resistance to drugs (including mutagens). A better design of antiviral therapies will still require an improvement of our knowledge about lethal mutagenesis.

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“…In general, well-adapted viral populations propagated in constant environments under the action of high concentration of mutagens are extinguished or reduce their infectivity (Moreno et al 2012;Perales et al 2011a;Arias et al 2013;Arribas et al 2011). However, when the viral population is allowed to adapt to gradual increases in mutagen concentration, variants that better resist the drug can be selected, and the population may escape extinction (Arias et al 2008;Arribas et al 2011;Agudo et al 2010;Pfeiffer and Kirkegaard 2003).…”

Section: The Complex Response Of Rna Viruses To Increases In the Mutamentioning

confidence: 99%

Getting to Know Viral Evolutionary Strategies: Towards the Next Generation of Quasispecies Models

Manrubia

Lázaro

2015

Current Topics in Microbiology and Immunology

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Viral populations are formed by complex ensembles of genomes with broad phenotypic diversity. The adaptive strategies deployed by these ensembles are multiple and often cannot be predicted a priori. Our understanding of viral dynamics is mostly based on two kinds of empirical approaches: one directed towards characterizing molecular changes underlying fitness changes and another focused on population-level responses. Simultaneously, theoretical efforts are directed towards developing a formal picture of viral evolution by means of more realistic fitness landscapes and reliable population dynamics models. New technologies, chiefly the use of next-generation sequencing and related tools, are opening avenues connecting the molecular and the population levels. In the near future, we hope to be witnesses of an integration of these still decoupled approaches, leading into more accurate and realistic quasispecies models able to capture robust generalities and endowed with a satisfactory predictive power.

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Mutagenesis-Mediated Virus Extinction: Virus-Dependent Effect of Viral Load on Sensitivity to Lethal Defection

Cited by 25 publications

References 88 publications

Extinction of Hepatitis C Virus by Ribavirin in Hepatoma Cells Involves Lethal Mutagenesis

Extinction of Hepatitis C Virus by Ribavirin in Hepatoma Cells Involves Lethal Mutagenesis

Theories of Lethal Mutagenesis: From Error Catastrophe to Lethal Defection

Getting to Know Viral Evolutionary Strategies: Towards the Next Generation of Quasispecies Models

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