Beneficial Effects of Population Bottlenecks in an RNA Virus Evolving at Increased Error Rate

Cases-González, Clara E.; Arribas, María Teresa Verde; Domingo, Esteban; Lázaro, Ester

doi:10.1016/j.jmb.2008.10.014

Cited by 34 publications

(31 citation statements)

References 47 publications

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“…This result is similar to previous findings with a variety RNA viruses exposed to nucleoside analogues (5,8,9,11,15,30,31,39,55) although here we failed to trigger lethal mutagenesis. Higher efficiency of 5-FU incorporation into RNA than into DNA may offer an explanation.…”

Section: Discussionsupporting

confidence: 93%

“…Another possible explanation for our inability to sufficiently debilitate the virus is that the founder clone was highly nonadapted. Work with X174 and other viruses has shown that serial passaging at low population sizes tends to favor the accumulation of deleterious mutations but fails to reduce fitness in already debilitated viruses because beneficial mutations are more frequent in low-fitness genetic backgrounds and can offset the effects of deleterious mutation accumulation (8,38,56).…”

Section: Discussionmentioning

confidence: 99%

“…RNA viruses are situated at the top of this range, and it is commonly accepted that their mutation rates cannot be increased further without compromising viral fitness. Supporting this view, serial passages in the presence of nucleoside analogues or other mutagens have been shown to produce drastic fitness losses or even population extinction through lethal mutagenesis in a variety of RNA viruses including enteroviruses (11,30), aphthoviruses (55), hantaviruses (9), arenaviruses (31), lentiviruses (15,39), and leviviruses (5,8). This has led to the suggestion that lethal mutagenesis could be used as a therapeutic strategy against RNA viruses (19,43) although several resistance mechanisms have already been described, such as the ability to selectively exclude nucleoside analogues from the polymerase active site, an overall increase in replication fidelity, or increased tolerance to mutation (2,4,10,29,45,51,54).…”

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confidence: 99%

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Nucleoside Analogue Mutagenesis of a Single-Stranded DNA Virus: Evolution and Resistance

Domingo‐Calap

Pereira-Gómez

Sanjuán

2012

J Virol

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It has been well established that chemical mutagenesis has adverse fitness effects in RNA viruses, often leading to population extinction. This is mainly a consequence of the high RNA virus spontaneous mutation rates, which situate them close to the extinction threshold. Single-stranded DNA viruses are the fastest-mutating DNA-based systems, with per-nucleotide mutation rates close to those of some RNA viruses, but chemical mutagenesis has been much less studied in this type of viruses. Here, we serially passaged bacteriophage ϕX174 in the presence of the nucleoside analogue 5-fluorouracil (5-FU). We found that 5-FU was unable to trigger population extinction for the range of concentrations tested, but it negatively affected viral adaptability. The phage evolved partial drug resistance, and parallel nucleotide substitutions appearing in independently evolved lines were identified as candidate resistance mutations. Using site-directed mutagenesis, two single-nucleotide substitutions in the lysis protein E (T572C and A781G) were shown to be selectively advantageous in the presence of 5-FU. In RNA viruses, base analogue resistance is often mediated by changes in the viral polymerase, but this mechanism is not possible for ϕX174 and other single-stranded DNA viruses because they do not encode their own polymerase. In addition to increasing mutation rates, 5-FU produces a wide variety of cytotoxic effects at the levels of replication, transcription, and translation. We found that substitutions T572C and A781G lost their ability to confer 5-FU resistance after cells were supplemented with deoxythymidine, suggesting that their mechanism of action is at the DNA level. We hypothesize that regulation of lysis time may allow the virus to optimize progeny size in cells showing defects in DNA synthesis.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Nucleoside Analogue Mutagenesis of a Single-Stranded DNA Virus: Evolution and Resistance

Domingo‐Calap

Pereira-Gómez

Sanjuán

2012

J Virol

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“…A significant increase in the mutation rate has been, indeed, successful to cause the extinction of infectivity in many different viral systems (20,21), although the mechanisms through which extinction supervenes are diverse and related to a variety of molecular and population responses (22). In particular, increased mutagenesis can also bear beneficial effects for viral populations through an enhancement of their diversity, which promotes adaptation of low-fitness viruses (23) and facilitates the appearance of resistance mutants when an inhibitor of viral replication is present (24).…”

mentioning

confidence: 99%

Tempo and mode of inhibitor–mutagen antiviral therapies: A multidisciplinary approach

Iranzo

Perales

Domingo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The continuous emergence of drug-resistant viruses is a major obstacle for the successful treatment of viral infections, thus representing a persistent spur to the search for new therapeutic strategies. Among them, multidrug treatments are currently at the forefront of pharmaceutical, clinical, and computational investigation. Still, there are many unknowns in the way that different drugs interact among themselves and with the pathogen that they aim to control. Inspired by experimental studies with picornavirus, here, we discuss the performance of sequential vs. combination therapies involving two dissimilar drugs: the mutagen ribavirin and an inhibitor of viral replication, guanidine. Because a systematic analysis of viral response to drug doses demands a precious amount of time and resources, we present and analyze an in silico model describing the dynamics of the viral population under the action of the two drugs. The model predicts the response of the viral population to any dose combination, the optimal therapy to be used in each case, and the way to minimize the probability of appearance of resistant mutants. In agreement with the theoretical predictions, in vitro experiments with foot-and-mouth disease virus confirm that the suitability of simultaneous or sequential administration depends on the drug doses. In addition, intrinsic replicative characteristics of the virus (e.g., replication through RNA only or a DNA intermediate) play a key role to determine the appropriateness of a sequential or combination therapy. Knowledge of several model parameters can be derived by means of few, simple experiments, such that the model and its predictions can be extended to other viral systems.population dynamics | antiviral design | viral quasispecies | mutation | viral adaptation

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“…The above considerations indicate that it can depend on the environment, on the population size and on other parameters such as the diffusion of the virus in the medium in which it propagates. Spatial constraints, that are rarely taken into account (Altmeyer & McCaskill 2001;Aguirre & Manrubia 2008) can condition the degree of competition among genomes, the capacity of the virus to infect new cells and the degree of preservation of the resulting mutants, which have higher chances of surviving as diffusion decreases (Cases-González et al 2008). The critical mutation rate has a genetic component (determined by the actual mutation rate, the type of mutants produced and the interactions established among them) and a demographic component, ascribed to reductions in the population size caused by the deleterious effects that most mutations have on fitness.…”

Section: The Critical Mutation Rate: a Relative Conceptmentioning

confidence: 99%

Pathways to extinction: beyond the error threshold

Manrubia

Domingo

Lázaro

2010

Phil. Trans. R. Soc. B

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Since the introduction of the quasispecies and the error catastrophe concepts for molecular evolution by Eigen and their subsequent application to viral populations, increased mutagenesis has become a common strategy to cause the extinction of viral infectivity. Nevertheless, the high complexity of virus populations has shown that viral extinction can occur through several other pathways apart from crossing an error threshold. Increases in the mutation rate enhance the appearance of defective forms and promote the selection of mechanisms that are able to counteract the accelerated appearance of mutations. Current models of viral evolution take into account more realistic scenarios that consider compensatory and lethal mutations, a highly redundant genotype-to-phenotype map, rough fitness landscapes relating phenotype and fitness, and where phenotype is described as a set of interdependent traits. Further, viral populations cannot be understood without specifying the characteristics of the environment where they evolve and adapt. Altogether, it turns out that the pathways through which viral quasispecies go extinct are multiple and diverse.

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Beneficial Effects of Population Bottlenecks in an RNA Virus Evolving at Increased Error Rate

Cited by 34 publications

References 47 publications

Nucleoside Analogue Mutagenesis of a Single-Stranded DNA Virus: Evolution and Resistance

Nucleoside Analogue Mutagenesis of a Single-Stranded DNA Virus: Evolution and Resistance

Tempo and mode of inhibitor–mutagen antiviral therapies: A multidisciplinary approach

Pathways to extinction: beyond the error threshold

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