Effect of Ribavirin on the Mutation Rate and Spectrum of Hepatitis C Virus In Vivo

Cuevas, José M.; Gónzález-Candelas, Fernando; Moya, Andrés; Sanjuán, Rafael

doi:10.1128/jvi.00201-09

Cited by 146 publications

(146 citation statements)

References 43 publications

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“…Error catastrophe is defined as a loss of genetic fidelity during RNA virus replication that results in a lethal accumulation of errors. Ribavirin increases the level of genetic variation or mutation load in hantaviruses, polioviruses, and others in the presence of ribavirin in vitro, resulting in error catastrophe or lethal extinction once a specific level of mutation is achieved by the drug (18,(27)(28)(29)(30)34). Therefore, one might predict that coupled with normal within-host selection processes, ribavirin would be even more effective in causing error catastrophe or lethal extinction of the virus in vivo than in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we employed a lethal murine model of hantaviral disease with a prototypic HFRS virus, HTNV, to gain insight into viral replication and genetic variation over time with and without ribavirin treatment. Our research and that of others have shown that small molecules such as ribavirin increase the mutation load of the viral genome, which results in the extinction of the virus in vitro (18,(27)(28)(29)(30)34). Improving our understanding of how to drive a virus to extinction by increasing genetic variation by use of small antiviral molecules such as ribavirin (e.g., lethal mutagenesis) requires insight into how viruses evolve and adapt within different environments.…”

Section: Discussionmentioning

confidence: 99%

“…Additional targets for its antiviral activity have been shown, including capping (22), translation efficiency of viral mRNA (23), and a direct suppressive effect on the viral polymerase activity (24)(25)(26). Ribavirin can also act as a potent RNA virus mutagen for several RNA viruses and can cause error-prone replication (18,(27)(28)(29)(30). In addition to targeting the purine metabolic pathway and viral enzymes, recent studies suggest that ribavirin may act by promoting a type 1 immune response (31).…”

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confidence: 99%

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The Murine Model for Hantaan Virus-Induced Lethal Disease Shows Two Distinct Paths in Viral Evolutionary Trajectory with and without Ribavirin Treatment

Chung

Västermark

Camp

et al. 2013

J Virol

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eIn vitro, ribavirin acts as a lethal mutagen in Hantaan virus (HTNV)-infected Vero E6 cells, resulting in an increased mutation load and viral population extinction. In this study, we asked whether ribavirin treatment in the lethal, suckling mouse model of HTNV infection would act similarly. The HTNV genomic RNA (vRNA) copy number and infectious virus were measured in lungs of untreated and ribavirin-treated mice. In untreated, HTNV-infected mice, the vRNA copy number increased for 10 days postinfection (dpi) and thereafter remained constant through 26 dpi. Surprisingly, in ribavirin-treated, HTNV-infected mice, vRNA levels were similar to those in untreated mice between 10 and 26 dpi. Infectious virus levels, however, were different: in ribavirin-treated mice, the amount of infectious HTNV was significantly decreased relative to that in untreated mice, suggesting that ribavirin reduced the specific infectivity of the virus (amount of infectious virus produced per vRNA copy). Mutational analysis revealed a ribavirin-associated elevation in mutation frequency in HTNV vRNA similar to that previously reported in vitro. Codon-based analyses of rates of nonsynonymous (dN) and synonymous (dS) substitutions in the S segment revealed a positive selection for codons within the HTNV N protein gene in the ribavirin-treated vRNA population. In contrast, the vRNA population in untreated, HTNV-infected mice showed a lower level of diversity, reflecting purifying selection for the wild-type genome. In summary, these experiments show two different evolutionary paths that Hantavirus may take during infection in a lethal murine model of disease, as well as the importance of the in vivo host environment in the evolution of the virus, which was not apparent in our prior in vitro model system.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Murine Model for Hantaan Virus-Induced Lethal Disease Shows Two Distinct Paths in Viral Evolutionary Trajectory with and without Ribavirin Treatment

Chung

Västermark

Camp

et al. 2013

J Virol

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“…In other words, this method provides an estimate of mutation rate per replication event (m/b/r) rather than by generation, as in the first method. Following Cuevas et al (2009), it is possible to calculate a mutation rate for the ith amplicon using the expression…”

Section: Virus and Plantsmentioning

confidence: 99%

The Rate and Spectrum of Spontaneous Mutations in a Plant RNA Virus

Tromas

Elena

2010

Genetics

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Knowing mutation rates and the molecular spectrum of spontaneous mutations is important to understanding how the genetic composition of viral populations evolves. Previous studies have shown that the rate of spontaneous mutations for RNA viruses widely varies between 0.01 and 2 mutations per genome and generation, with plant RNA viruses always occupying the lower side of this range. However, this peculiarity of plant RNA viruses is based on a very limited number of studies. Here we analyze the spontaneous mutational spectrum and the mutation rate of Tobacco etch potyvirus, a model system of positive sense RNA viruses. Our experimental setup minimizes the action of purifying selection on the mutational spectrum, thus giving a picture of what types of mutations are produced by the viral replicase. As expected for a neutral target, we found that transitions and nonsynonymous (including a few stop codons and small deletions) mutations were the most abundant type. This spectrum was notably different from the one previously described for another plant virus. We have estimated that the spontaneous mutation rate for this virus was in the range 10 À6 À10À5 mutations per site and generation. Our estimates are in the same biological ballpark that previous values reported for plant RNA viruses. This finding gives further support to the idea that plant RNA viruses may have lower mutation rates than their animal counterparts.T HE rate of spontaneous mutation is a key parameter to understanding the genetic structure of populations over time. Mutation represents the primary source of genetic variation on which natural selection and genetic drift operate. Although the exact value of the mutation rate is important for several evolutionary theories, accurate estimates are available only for a handful of organisms. RNA viruses show mutation rates that are orders of magnitude higher than those of their DNA-based hosts and in the range of 0

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“…HCV is classified into six major genetic groups, each further divided into more closely related subtypes, and within an infected individual the virus exists as a constantly evolving quasispecies (40). The genetic variability of HCV is owed to a high viral replication rate and an error-prone RNA-dependent polymerase (NS5B) with an estimated mutation rate of 10 Ϫ4 per nucleotide per generation (12).…”

mentioning

confidence: 99%

Conserved Glycine 33 Residue in Flexible Domain I of Hepatitis C Virus Core Protein Is Critical for Virus Infectivity

Angus

Loquet

Stack

et al. 2012

J Virol

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Hepatitis C virus core protein forms the viral nucleocapsid and plays a critical role in the formation of infectious particles. In this study, we demonstrate that the highly conserved residue G33, located within domain 1 of the core protein, is important for the production of cell culture-infectious virus (HCVcc). Alanine substitution at this position in the JFH1 genome did not alter viral RNA replication but reduced infectivity by ϳ2 logs. Virus production by this core mutant could be rescued by compensatory mutations located immediately upstream and downstream of the original G33A mutation. The examination of the helixloop-helix motif observed in the core protein structure (residues 15 to 41; Protein Data Bank entry 1CWX) indicated that the residues G33 and F24 are in close contact with each other, and that the G33A mutation induces a steric clash with F24. Molecular simulations revealed that the compensatory mutations increase the helix-loop-helix flexibility, allowing rescue of the core active conformation required for efficient virus production. Taken together, these data highlight the plasticity of core domain 1 conformation and illustrate the relationship between its structural tolerance to mutations and virus infectivity.

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Effect of Ribavirin on the Mutation Rate and Spectrum of Hepatitis C Virus In Vivo

Cited by 146 publications

References 43 publications

The Murine Model for Hantaan Virus-Induced Lethal Disease Shows Two Distinct Paths in Viral Evolutionary Trajectory with and without Ribavirin Treatment

The Murine Model for Hantaan Virus-Induced Lethal Disease Shows Two Distinct Paths in Viral Evolutionary Trajectory with and without Ribavirin Treatment

The Rate and Spectrum of Spontaneous Mutations in a Plant RNA Virus

Conserved Glycine 33 Residue in Flexible Domain I of Hepatitis C Virus Core Protein Is Critical for Virus Infectivity

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