Complications of RNA Heterogeneity for the Engineering of Virus Vaccines and Antiviral Agents

Domingo, Esteban; Holland, John J.

doi:10.1007/978-1-4615-3424-2_2

Cited by 45 publications

(43 citation statements)

References 132 publications

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“…Ever since the quasispecies dynamics were revealed as general for pathogenic RNA viruses and retroviruses, the problem of treatment failure because of selection of drug-escape viral mutants was recognized (25). Several approaches have been used in medical practice to minimize selection of viral mutants resistant to antiviral agents.…”

Section: Discussionmentioning

confidence: 99%

“…The most successful strategy was the implementation of combination therapy involving the simultaneous administration of two or more drugs directed to different viral targets. The advantages of combination therapy over monotherapy stem from basic statistical considerations on the frequency of generation of multidrug-resistant mutants (25). The advantage of combination vs. various regimens of sequential or treatment interruption (structured treatment interruptions or drug holidays) regimens has been supported by results of multiple clinical trials as well as theoretical models of viral dynamics (5,11,(26)(27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…Genetic variation of RNA viruses through mutation, homologous and nonhomologous recombination, and genome segment reassortment constitutes a major difficulty for disease prevention and control (16,17,19). Difficulties arise from adaptability, which has its origins in the continuous production of mutant genomes, which favors a process of competition and selection of those mutant distributions best adapted to a given environment (17,21).…”

Section: Discussionmentioning

confidence: 99%

Preextinction Viral RNA Can Interfere with Infectivity

Lopez

Arias

Pariente

et al. 2004

J Virol

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111

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When the error rate during the copying of genetic material exceeds a threshold value, the genetic information cannot be maintained. This concept is the basis of a new antiviral strategy termed lethal mutagenesis or virus entry into error catastrophe. Critical for its success is preventing survival of residual infectious virus or virus mutants that escape the transition into error catastrophe. Here we document that mutated, preextinction foot-and-mouth disease virus (FMDV) RNA can interfere with and delay viral production up to 30 h when cotransfected in BHK-21 cells with standard RNA. Interference depended on the physical integrity of preextinction RNA and was not observed with unrelated RNAs or with nonmutated, defective FMDV RNA. These results suggest that this type of interference requires large size, preextinction FMDV RNA and is mediated neither by small interfering RNAs nor by RNAs that can compete with infectious RNA for host cell factors. A model based on the aberrant expression of mutated RNA as it is expected to occur in the initial stages of the transition into error catastrophe is proposed. Interference mediated by preextinction RNA indicates an advantage of mutagenesis versus inhibition in preventing the survival of virus escape mutants during antiviral treatments.High mutation rates and quasispecies dynamics (17,21,23) confer great adaptability to RNA viruses and represent a major obstacle for the prevention and control of RNA viral diseases (17, 25). However, theoretical studies have provided evidence that for any replication system there is a maximum error rate compatible with maintenance of the information encoded in the replicating genome (2,22,23,37,46). The larger the complexity of the genome, the higher the copying fidelity needed to maintain the encoded information. The irreversible transition into loss of genetic information is termed entry into error catastrophe, and the critical average error rate at the transition point is the error threshold (2,22,23,37,46). This concept has encouraged research in a new antiviral strategy termed lethal mutagenesis (12,22,29,32). In the case of viruses, crossing the error threshold should result in a transition from a productive to an abortive infection. Virus extinction associated with enhanced mutagenesis has been documented with a variety of virus-host systems (1, 12, 13, 27, 29, 31-34, 39, 43, 44; for reviews, see references 16, 22, and 26), including prevention of the establishment of a persistent lymphocytic choriomeningitis virus (LCMV) infection in vivo (42).Studies with the animal picornavirus foot-and-mouth disease virus (FMDV) in cell culture have established that virus extinction through enhanced mutagenesis is favored by low viral load and low viral fitness (44). As a consequence, combination treatments involving a mutagenic agent and antiviral inhibitors were more effective than a mutagenic agent alone in driving FMDV to extinction (39). When the mutagenic activity was insufficient for a given fitness level of FMDV, inhibitor-resistant, e...

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“…The need of combination therapy with two or more inhibitors to limit the chances of generating and selecting inhibitorresistant mutants in viral quasispecies has been emphasized (17,19,29,33). Early experiments suggested a more effective control of influenza virus by a combined vaccine-antiviral strategy (32,45,70).…”

Section: Discussionmentioning

confidence: 99%

Efficient Virus Extinction by Combinations of a Mutagen and Antiviral Inhibitors

Pariente

Sierra

Löwenstein

et al. 2001

J Virol

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144

190

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An increase in the mutation rate during replication of RNA viruses can result in a decrease of viral infectivity and occasional virus extinction (11,34,39,40,60). Studies with the important animal pathogen foot-and-mouth disease virus (FMDV)-a member of the Picornaviridae family (53, 63)-have shown that a small replicative population size and low viral fitness favored virus extinction (60). This was documented with single and multiple passages of FMDVs differing up to 10 6 -fold in relative fitness in the absence or presence of the mutagenic base analogs 5-fluorourocil (FU) or 5-azacytidine, individually or in combination (59, 60). Mutagenic treatments resulted in occasional, not systematic, viral extinction, while parallel passages in the absence of mutagens never led to loss of infectivity, no matter how low the initial viral population size and fitness were (59, 60). These results suggested the possibility that a combination of an antiviral inhibitor, to reduce the replicative load of virus, and a mutagenic agent could be more effective in producing viral extinction than a mutagenic agent used in isolation. To test this possibility we have studied the effect of the mutagenic base analog FU and the antiviral inhibitors guanidine hydrochloride (G) and heparin (H) on the infectivity of FMDV clones and populations depicting a wide range of relative fitness values. FU has been shown to be mutagenic for a number of RNA viruses (6,20,31,34,51,71), including FMDV (59,60). G at millimolar concentrations blocks the replication of picornaviruses (5,7,15,49,52,55), arboviruses (27), and several plant viruses (13, 67). In poliovirus, the target of G is the ATPase activity of nonstructural protein 2C (49), a protein involved in viral replication and encapsidation. In FMDV, amino acid substitutions at 2C have also been associated with resistance to G (56). Heparins are sulfated polysaccharides (9) which bind FMDV when the virus has been passaged in cell culture and has adapted to using heparan sulfate (HS) as a receptor (2,35,54). Adaptation to use of HS as a receptor has been associated with substitutions which lead to positively charged amino acids at exposed positions of the capsid (2, 54).Here we report that high-frequency extinctions of FMDV of low and intermediate fitness values can be achieved with a combination of FU and G but not with either drug alone. Extinction of high-fitness FMDV populations required a triple combination of G and H together with FU. Mutation frequencies in the mutant spectrum of three genomic regions of a preextinction population obtained by the combined action of an inhibitor and a mutagen were compared to values in genomes passaged in standard conditions and also to values previously determined for FMDV populations subjected to one or multiple passages in the presence of FU (60). We found that mutation frequencies increased up to fourfold. There was also a statistically significant increase in the number of mutations in preextinction populations with respect to control populations, and the ...

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Complications of RNA Heterogeneity for the Engineering of Virus Vaccines and Antiviral Agents

Cited by 45 publications

References 132 publications

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

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

Preextinction Viral RNA Can Interfere with Infectivity

Efficient Virus Extinction by Combinations of a Mutagen and Antiviral Inhibitors

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