1887

Abstract

Low fidelity replication and the absence of error-repair activities in RNA viruses result in complex and adaptable ensembles of related genomes in the viral population, termed quasispecies, with important implications for natural infections. Theoretical predictions suggested that elevated replication error rates in RNA viruses might be near to a maximum compatible with viral viability. This fact encouraged the use of mutagenic nucleosides as a new antiviral strategy to induce viral extinction through increased replication error rates. Despite extensive evidence of lethal mutagenesis of RNA viruses by different mutagenic compounds, a detailed picture of the infectivity of individual genomes and its relationship with the mutations accumulated is lacking. Here, we report a molecular analysis of a foot-and-mouth disease virus population previously subjected to heavy mutagenesis to determine whether a correlation between increased mutagenesis and decreased fitness existed. Plaque-purified viruses isolated from a ribavirin-treated quasispecies presented decreases of up to 200-fold in infectivity relative to clones in the reference population, associated with an overall eightfold increase in the mutation frequency. This observation suggests that individual infectious genomes of a quasispecies subjected to increased mutagenesis lose infectivity by their continuous mutagenic ‘poisoning’. These results support the lethal defection model of virus extinction and the practical use of chemical mutagens as antiviral treatment. Even when extinction is not achieved, mutagenesis can decrease the infectivity of surviving virus, and facilitate their clearance by host immune responses or complementing antiviral approaches.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.049171-0
2013-04-01
2019-09-17
Loading full text...

Full text loading...

/deliver/fulltext/jgv/94/4/817.html?itemId=/content/journal/jgv/10.1099/vir.0.049171-0&mimeType=html&fmt=ahah

References

  1. Agudo R., Arias A., Domingo E.. ( 2009;). 5-Fluorouracil in lethal mutagenesis of foot-and-mouth disease virus. . Future Medical Chemistry 1:, 529–539. [CrossRef]
    [Google Scholar]
  2. Agudo R., Ferrer-Orta C., Arias A., de la Higuera I., Perales C., Pérez-Luque R., Verdaguer N., Domingo E.. ( 2010;). A multi-step process of viral adaptation to a mutagenic nucleoside analogue by modulation of transition types leads to extinction-escape. . PLoS Pathog 6:, e1001072. [CrossRef][PubMed]
    [Google Scholar]
  3. Airaksinen A., Pariente N., Menéndez-Arias L., Domingo E.. ( 2003;). Curing of foot-and-mouth disease virus from persistently infected cells by ribavirin involves enhanced mutagenesis. . Virology 311:, 339–349. [CrossRef][PubMed]
    [Google Scholar]
  4. Anderson J. P., Daifuku R., Loeb L. A.. ( 2004;). Viral error catastrophe by mutagenic nucleosides. . Annu Rev Microbiol 58:, 183–205. [CrossRef][PubMed]
    [Google Scholar]
  5. Arias A., Ruiz-Jarabo C. M., Escarmís C., Domingo E.. ( 2004;). Fitness increase of memory genomes in a viral quasispecies. . J Mol Biol 339:, 405–412. [CrossRef][PubMed]
    [Google Scholar]
  6. Arias A., Agudo R., Ferrer-Orta C., Pérez-Luque R., Airaksinen A., Brocchi E., Domingo E., Verdaguer N., Escarmís C.. ( 2005;). Mutant viral polymerase in the transition of virus to error catastrophe identifies a critical site for RNA binding. . J Mol Biol 353:, 1021–1032. [CrossRef][PubMed]
    [Google Scholar]
  7. Arias A., Arnold J. J., Sierra M., Smidansky E. D., Domingo E., Cameron C. E.. ( 2008;). Determinants of RNA-dependent RNA polymerase (in)fidelity revealed by kinetic analysis of the polymerase encoded by a foot-and-mouth disease virus mutant with reduced sensitivity to ribavirin. . J Virol 82:, 12346–12355. [CrossRef][PubMed]
    [Google Scholar]
  8. Arnold J. J., Vignuzzi M., Stone J. K., Andino R., Cameron C. E.. ( 2005;). Remote site control of an active site fidelity checkpoint in a viral RNA-dependent RNA polymerase. . J Biol Chem 280:, 25706–25716. [CrossRef][PubMed]
    [Google Scholar]
  9. Asahina Y., Izumi N., Enomoto N., Uchihara M., Kurosaki M., Onuki Y., Nishimura Y., Ueda K., Tsuchiya K.. & other authors ( 2005;). Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C. . J Hepatol 43:, 623–629. [CrossRef][PubMed]
    [Google Scholar]
  10. Batschelet E., Domingo E., Weissmann C.. ( 1976;). The proportion of revertant and mutant phage in a growing population, as a function of mutation and growth rate. . Gene 1:, 27–32. [CrossRef][PubMed]
    [Google Scholar]
  11. Bull R. A., Eden J. S., Rawlinson W. D., White P. A.. ( 2010;). Rapid evolution of pandemic noroviruses of the GII.4 lineage. . PLoS Pathog 6:, e1000831. [CrossRef][PubMed]
    [Google Scholar]
  12. Carrillo C., Tulman E. R., Delhon G., Lu Z., Carreno A., Vagnozzi A., Kutish G. F., Rock D. L.. ( 2005;). Comparative genomics of foot-and-mouth disease virus. . J Virol 79:, 6487–6504. [CrossRef][PubMed]
    [Google Scholar]
  13. Castro C., Arnold J. J., Cameron C. E.. ( 2005;). Incorporation fidelity of the viral RNA-dependent RNA polymerase: a kinetic, thermodynamic and structural perspective. . Virus Res 107:, 141–149. [CrossRef][PubMed]
    [Google Scholar]
  14. Cencic R., Mayer C., Juliano M. A., Juliano L., Konrat R., Kontaxis G., Skern T.. ( 2007;). Investigating the substrate specificity and oligomerisation of the leader protease of foot and mouth disease virus using NMR. . J Mol Biol 373:, 1071–1087. [CrossRef][PubMed]
    [Google Scholar]
  15. Chevaliez S., Brillet R., Lázaro E., Hézode C., Pawlotsky J. M.. ( 2007;). Analysis of ribavirin mutagenicity in human hepatitis C virus infection. . J Virol 81:, 7732–7741. [CrossRef][PubMed]
    [Google Scholar]
  16. Clay P. G., McRae M., Laurent J. P.. ( 2011;). Safety, tolerability, and pharmacokinetics of KP-1461 in phase I clinical studies: a single oral dose study in non-HIV-infected adults, and a 14-day dose-escalating study in highly antiretroviral-experienced HIV-infected adults. . J Int Assoc Physicians AIDS Care (Chic) 10:, 232–238. [CrossRef][PubMed]
    [Google Scholar]
  17. Contreras A. M., Hiasa Y., He W., Terella A., Schmidt E. V., Chung R. T.. ( 2002;). Viral RNA mutations are region specific and increased by ribavirin in a full-length hepatitis C virus replication system. . J Virol 76:, 8505–8517. [CrossRef][PubMed]
    [Google Scholar]
  18. Crotty S., Maag D., Arnold J. J., Zhong W., Lau J. Y., Hong Z., Andino R., Cameron C. E.. ( 2000;). The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. . Nat Med 6:, 1375–1379. [CrossRef][PubMed]
    [Google Scholar]
  19. Cuevas J. M., González-Candelas F., Moya A., Sanjuán R.. ( 2009;). Effect of ribavirin on the mutation rate and spectrum of hepatitis C virus in vivo. . J Virol 83:, 5760–5764. [CrossRef][PubMed]
    [Google Scholar]
  20. de la Torre J. C., Martínez-Salas E., Diez J., Villaverde A., Gebauer F., Rocha E., Dávila M., Domingo E.. ( 1988;). Coevolution of cells and viruses in a persistent infection of foot-and-mouth disease virus in cell culture. . J Virol 62:, 2050–2058.[PubMed]
    [Google Scholar]
  21. Dixit N. M., Layden-Almer J. E., Layden T. J., Perelson A. S.. ( 2004;). Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. . Nature 432:, 922–924. [CrossRef][PubMed]
    [Google Scholar]
  22. Domingo E.. ( 2000;). Viruses at the edge of adaptation. . Virology 270:, 251–253. [CrossRef][PubMed]
    [Google Scholar]
  23. Domingo E.. ( 2007;). Virus evolution. . In Fields Virology, , 5th edn., pp. 389–421. Edited by Knipe D. M., Howley P. M... Philadelphia:: LWW;.
    [Google Scholar]
  24. Domingo E., Martin V., Perales C., Grande-Pérez A., García-Arriaza J., Arias A.. ( 2006;). Viruses as quasispecies: biological implications. . Curr Top Microbiol Immunol 299:, 51–82. [CrossRef][PubMed]
    [Google Scholar]
  25. Domingo E., Sheldon J., Perales C.. ( 2012;). Viral quasispecies evolution. . Microbiol Mol Biol Rev 76:, 159–216. [CrossRef][PubMed]
    [Google Scholar]
  26. Drake J. W., Holland J. J.. ( 1999;). Mutation rates among RNA viruses. . Proc Natl Acad Sci U S A 96:, 13910–13913. [CrossRef][PubMed]
    [Google Scholar]
  27. Eigen M.. ( 2002;). Error catastrophe and antiviral strategy. . Proc Natl Acad Sci U S A 99:, 13374–13376. [CrossRef][PubMed]
    [Google Scholar]
  28. Eigen M., Biebricher C. K.. ( 1988;). Sequence space and quasispecies distribution. . In RNA Genetics, vol. 3., pp. 211–245. Edited by Domingo E., Ahlquist P., Holland J. J... Boca Raton, FL:: CRC Press;.
    [Google Scholar]
  29. Eigen M., Schuster P.. ( 1979;). The Hypercycle. A Principle of Natural Self-Organization. Berlin:: Springer;.
    [Google Scholar]
  30. Escarmís C., Dávila M., Charpentier N., Bracho A., Moya A., Domingo E.. ( 1996;). Genetic lesions associated with Muller’s ratchet in an RNA virus. . J Mol Biol 264:, 255–267. [CrossRef][PubMed]
    [Google Scholar]
  31. Escarmís C., Dávila M., Domingo E.. ( 1999;). Multiple molecular pathways for fitness recovery of an RNA virus debilitated by operation of Muller’s ratchet. . J Mol Biol 285:, 495–505. [CrossRef][PubMed]
    [Google Scholar]
  32. Escarmís C., Lázaro E., Manrubia S. C.. ( 2006;). Population bottlenecks in quasispecies dynamics. . Curr Top Microbiol Immunol 299:, 141–170. [CrossRef][PubMed]
    [Google Scholar]
  33. Escarmís C., Lázaro E., Arias A., Domingo E.. ( 2008;). Repeated bottleneck transfers can lead to non-cytocidal forms of a cytopathic virus: implications for viral extinction. . J Mol Biol 376:, 367–379. [CrossRef][PubMed]
    [Google Scholar]
  34. Ferrer-Orta C., Arias A., Pérez-Luque R., Escarmís C., Domingo E., Verdaguer N.. ( 2007;). Sequential structures provide insights into the fidelity of RNA replication. . Proc Natl Acad Sci U S A 104:, 9463–9468. [CrossRef][PubMed]
    [Google Scholar]
  35. Ferrer-Orta C., Sierra M., Agudo R., de la Higuera I., Arias A., Pérez-Luque R., Escarmís C., Domingo E., Verdaguer N.. ( 2010;). Structure of foot-and-mouth disease virus mutant polymerases with reduced sensitivity to ribavirin. . J Virol 84:, 6188–6199. [CrossRef][PubMed]
    [Google Scholar]
  36. Gnädig N. F., Beaucourt S., Campagnola G., Bordería A. V., Sanz-Ramos M., Gong P., Blanc H., Peersen O. B., Vignuzzi M.. ( 2012;). Coxsackievirus B3 mutator strains are attenuated in vivo. . Proc Natl Acad Sci U S A 109:, E2294–E2303. [CrossRef][PubMed]
    [Google Scholar]
  37. González-López C., Arias A., Pariente N., Gómez-Mariano G., Domingo E.. ( 2004;). Preextinction viral RNA can interfere with infectivity. . J Virol 78:, 3319–3324. [CrossRef][PubMed]
    [Google Scholar]
  38. González-López C., Gómez-Mariano G., Escarmís C., Domingo E.. ( 2005;). Invariant aphthovirus consensus nucleotide sequence in the transition to error catastrophe. . Infect Genet Evol 5:, 366–374. [CrossRef][PubMed]
    [Google Scholar]
  39. Graci J. D., Cameron C. E.. ( 2008;). Therapeutically targeting RNA viruses via lethal mutagenesis. . Future Virol 3:, 553–566. [CrossRef][PubMed]
    [Google Scholar]
  40. Grande-Pérez A., Sierra S., Castro M. G., Domingo E., Lowenstein P. R.. ( 2002;). Molecular indetermination in the transition to error catastrophe: systematic elimination of lymphocytic choriomeningitis virus through mutagenesis does not correlate linearly with large increases in mutant spectrum complexity. . Proc Natl Acad Sci U S A 99:, 12938–12943. [CrossRef][PubMed]
    [Google Scholar]
  41. Grande-Pérez A., Gómez-Mariano G., Lowenstein P. R., Domingo E.. ( 2005a;). Mutagenesis-induced, large fitness variations with an invariant arenavirus consensus genomic nucleotide sequence. . J Virol 79:, 10451–10459. [CrossRef][PubMed]
    [Google Scholar]
  42. Grande-Pérez A., Lázaro E., Lowenstein P., Domingo E., Manrubia S. C.. ( 2005b;). Suppression of viral infectivity through lethal defection. . Proc Natl Acad Sci U S A 102:, 4448–4452. [CrossRef][PubMed]
    [Google Scholar]
  43. Harris K. S., Brabant W., Styrchak S., Gall A., Daifuku R.. ( 2005;). KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. . Antiviral Res 67:, 1–9. [CrossRef][PubMed]
    [Google Scholar]
  44. Hicks C., Clay P., Redfield R. R., Lalezari J. P., Liporace R., Schneider S., Sension M., McRae M., Laurent J. P.. ( 2012;). Safety, tolerability, and efficacy of KP-1461 as monotherapy for 124 days in antiretroviral-experienced, HIV type 1-infected subjects. . AIDS Res Hum Retroviruses 120827084548003. (Epub ahead of print). [CrossRef][PubMed]
    [Google Scholar]
  45. Holland J., Spindler K., Horodyski F., Grabau E., Nichol S., VandePol S.. ( 1982;). Rapid evolution of RNA genomes. . Science 215:, 1577–1585. [CrossRef][PubMed]
    [Google Scholar]
  46. Holland J. J., Domingo E., de la Torre J. C., Steinhauer D. A.. ( 1990;). Mutation frequencies at defined single codon sites in vesicular stomatitis virus and poliovirus can be increased only slightly by chemical mutagenesis. . J Virol 64:, 3960–3962.[PubMed]
    [Google Scholar]
  47. Kanda T., Yokosuka O., Imazeki F., Tanaka M., Shino Y., Shimada H., Tomonaga T., Nomura F., Nagao K.. & other authors ( 2004;). Inhibition of subgenomic hepatitis C virus RNA in Huh-7 cells: ribavirin induces mutagenesis in HCV RNA. . J Viral Hepat 11:, 479–487. [CrossRef][PubMed]
    [Google Scholar]
  48. Lauring A. S., Andino R.. ( 2010;). Quasispecies theory and the behavior of RNA viruses. . PLoS Pathog 6:, e1001005. [CrossRef][PubMed]
    [Google Scholar]
  49. Lázaro E., Escarmís C., Pérez-Mercader J., Manrubia S. C., Domingo E.. ( 2003;). Resistance of virus to extinction on bottleneck passages: study of a decaying and fluctuating pattern of fitness loss. . Proc Natl Acad Sci U S A 100:, 10830–10835. [CrossRef][PubMed]
    [Google Scholar]
  50. Levi L. I., Gnädig N. F., Beaucourt S., McPherson M. J., Baron B., Arnold J. J., Vignuzzi M.. ( 2010;). Fidelity variants of RNA dependent RNA polymerases uncover an indirect, mutagenic activity of amiloride compounds. . PLoS Pathog 6:, e1001163. [CrossRef][PubMed]
    [Google Scholar]
  51. Loeb L. A., Essigmann J. M., Kazazi F., Zhang J., Rose K. D., Mullins J. I.. ( 1999;). Lethal mutagenesis of HIV with mutagenic nucleoside analogs. . Proc Natl Acad Sci U S A 96:, 1492–1497. [CrossRef][PubMed]
    [Google Scholar]
  52. Lutchman G., Danehower S., Song B. C., Liang T. J., Hoofnagle J. H., Thomson M., Ghany M. G.. ( 2007;). Mutation rate of the hepatitis C virus NS5B in patients undergoing treatment with ribavirin monotherapy. . Gastroenterology 132:, 1757–1766. [CrossRef][PubMed]
    [Google Scholar]
  53. Maag D., Castro C., Hong Z., Cameron C. E.. ( 2001;). Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. . J Biol Chem 276:, 46094–46098. [CrossRef][PubMed]
    [Google Scholar]
  54. Mahy B. W.. ( 2005;). Introduction and history of foot-and-mouth disease virus. . Curr Top Microbiol Immunol 288:, 1–8. [CrossRef][PubMed]
    [Google Scholar]
  55. Martín V., Grande-Pérez A., Domingo E.. ( 2008;). No evidence of selection for mutational robustness during lethal mutagenesis of lymphocytic choriomeningitis virus. . Virology 378:, 185–192. [CrossRef][PubMed]
    [Google Scholar]
  56. Martín V., Abia D., Domingo E., Grande-Pérez A.. ( 2010;). An interfering activity against lymphocytic choriomeningitis virus replication associated with enhanced mutagenesis. . J Gen Virol 91:, 990–1003. [CrossRef][PubMed]
    [Google Scholar]
  57. Más A., López-Galíndez C., Cacho I., Gómez J., Martínez M. A.. ( 2010;). Unfinished stories on viral quasispecies and Darwinian views of evolution. . J Mol Biol 397:, 865–877. [CrossRef][PubMed]
    [Google Scholar]
  58. Mateo R., Díaz A., Baranowski E., Mateu M. G.. ( 2003;). Complete alanine scanning of intersubunit interfaces in a foot-and-mouth disease virus capsid reveals critical contributions of many side chains to particle stability and viral function. . J Biol Chem 278:, 41019–41027. [CrossRef][PubMed]
    [Google Scholar]
  59. McFadden N., Bailey D., Carrara G., Benson A., Chaudhry Y., Shortland A., Heeney J., Yarovinsky F., Simmonds P.. & other authors ( 2011;). Norovirus regulation of the innate immune response and apoptosis occurs via the product of the alternative open reading frame 4. . PLoS Pathog 7:, e1002413. [CrossRef][PubMed]
    [Google Scholar]
  60. Moreno H., Gallego I., Sevilla N., de la Torre J. C., Domingo E., Martín V.. ( 2011;). Ribavirin can be mutagenic for arenaviruses. . J Virol 85:, 7246–7255. [CrossRef][PubMed]
    [Google Scholar]
  61. Moriyama K., Suzuki T., Negishi K., Graci J. D., Thompson C. N., Cameron C. E., Watanabe M.. ( 2008;). Effects of introduction of hydrophobic group on ribavirin base on mutation induction and anti-RNA viral activity. . J Med Chem 51:, 159–166. [CrossRef][PubMed]
    [Google Scholar]
  62. Mullins J. I., Heath L., Hughes J. P., Kicha J., Styrchak S., Wong K. G., Rao U., Hansen A., Harris K. S.. & other authors ( 2011;). Mutation of HIV-1 genomes in a clinical population treated with the mutagenic nucleoside KP1461. . PLoS ONE 6:, e15135. [CrossRef][PubMed]
    [Google Scholar]
  63. O’Dea E. B., Keller T. E., Wilke C. O.. ( 2010;). Does mutational robustness inhibit extinction by lethal mutagenesis in viral populations?. PLOS Comput Biol 6:, e1000811. [CrossRef][PubMed]
    [Google Scholar]
  64. Parera M., Fernàndez G., Clotet B., Martínez M. A.. ( 2007;). HIV-1 protease catalytic efficiency effects caused by random single amino acid substitutions. . Mol Biol Evol 24:, 382–387. [CrossRef][PubMed]
    [Google Scholar]
  65. Pariente N., Sierra S., Lowenstein P. R., Domingo E.. ( 2001;). Efficient virus extinction by combinations of a mutagen and antiviral inhibitors. . J Virol 75:, 9723–9730. [CrossRef][PubMed]
    [Google Scholar]
  66. Perales C., Mateo R., Mateu M. G., Domingo E.. ( 2007;). Insights into RNA virus mutant spectrum and lethal mutagenesis events: replicative interference and complementation by multiple point mutants. . J Mol Biol 369:, 985–1000. [CrossRef][PubMed]
    [Google Scholar]
  67. Perales C., Agudo R., Domingo E.. ( 2009a;). Counteracting quasispecies adaptability: extinction of a ribavirin-resistant virus mutant by an alternative mutagenic treatment. . PLoS ONE 4:, e5554. [CrossRef][PubMed]
    [Google Scholar]
  68. Perales C., Agudo R., Tejero H., Manrubia S. C., Domingo E.. ( 2009b;). Potential benefits of sequential inhibitor-mutagen treatments of RNA virus infections. . PLoS Pathog 5:, e1000658. [CrossRef][PubMed]
    [Google Scholar]
  69. Perales C., Lorenzo-Redondo R., López-Galíndez C., Martínez M. A., Domingo E.. ( 2010;). Mutant spectra in virus behavior. . Future Virology 5:, 679–698. [CrossRef]
    [Google Scholar]
  70. Perales C., Henry M., Domingo E., Wain-Hobson S., Vartanian J. P.. ( 2011;). Lethal mutagenesis of foot-and-mouth disease virus involves shifts in sequence space. . J Virol 85:, 12227–12240. [CrossRef][PubMed]
    [Google Scholar]
  71. Perelson A. S., Layden T. J.. ( 2007;). Ribavirin: is it a mutagen for hepatitis C virus?. Gastroenterology 132:, 2050–2052. [CrossRef][PubMed]
    [Google Scholar]
  72. Pfeiffer J. K., Kirkegaard K.. ( 2003;). A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity. . Proc Natl Acad Sci U S A 100:, 7289–7294. [CrossRef][PubMed]
    [Google Scholar]
  73. Pfeiffer J. K., Kirkegaard K.. ( 2005;). Increased fidelity reduces poliovirus fitness and virulence under selective pressure in mice. . PLoS Pathog 1:, e11. [CrossRef][PubMed]
    [Google Scholar]
  74. Rowlands D. J. E.. ( 2003;). Foot-and-mouth disease. . Virus Res 91:, 1–161. [CrossRef]
    [Google Scholar]
  75. Ruiz-Jarabo C. M., Ly C., Domingo E., de la Torre J. C.. ( 2003;). Lethal mutagenesis of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). . Virology 308:, 37–47. [CrossRef][PubMed]
    [Google Scholar]
  76. Sanjuán R., Moya A., Elena S. F.. ( 2004;). The contribution of epistasis to the architecture of fitness in an RNA virus. . Proc Natl Acad Sci U S A 101:, 15376–15379. [CrossRef][PubMed]
    [Google Scholar]
  77. Sanjuán R., Cuevas J. M., Furió V., Holmes E. C., Moya A.. ( 2007;). Selection for robustness in mutagenized RNA viruses. . PLoS Genet 3:, e93. [CrossRef][PubMed]
    [Google Scholar]
  78. Sanz-Ramos M., Rodríguez-Calvo T., Sevilla N.. ( 2012;). Mutagenesis-mediated decrease of pathogenicity as a feature of the mutant spectrum of a viral population. . PLoS ONE 7:, e39941. [CrossRef][PubMed]
    [Google Scholar]
  79. Sierra S., Dávila M., Lowenstein P. R., Domingo E.. ( 2000;). Response of foot-and-mouth disease virus to increased mutagenesis: influence of viral load and fitness in loss of infectivity. . J Virol 74:, 8316–8323. [CrossRef][PubMed]
    [Google Scholar]
  80. Sierra M., Airaksinen A., González-López C., Agudo R., Arias A., Domingo E.. ( 2007;). Foot-and-mouth disease virus mutant with decreased sensitivity to ribavirin: implications for error catastrophe. . J Virol 81:, 2012–2024. [CrossRef][PubMed]
    [Google Scholar]
  81. Sobrino F., Domingo E. E.. ( 2004;). Foot-and-Mouth Disease: Current Perspectives. Wymondham, UK:: Horizon Bioscience;.
    [Google Scholar]
  82. Sobrino F., Dávila M., Ortín J., Domingo E.. ( 1983;). Multiple genetic variants arise in the course of replication of foot-and-mouth disease virus in cell culture. . Virology 128:, 310–318. [CrossRef][PubMed]
    [Google Scholar]
  83. Sorgeloos F., Vertommen D., Rider M. H., Michiels T.. ( 2011;). Theiler’s virus L protein is targeted to the mitochondrial outer membrane. . J Virol 85:, 3690–3694. [CrossRef][PubMed]
    [Google Scholar]
  84. Swetina J., Schuster P.. ( 1982;). Self-replication with errors. A model for polynucleotide replication. . Biophys Chem 16:, 329–345. [CrossRef][PubMed]
    [Google Scholar]
  85. Vignuzzi M., Stone J. K., Arnold J. J., Cameron C. E., Andino R.. ( 2006;). Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. . Nature 439:, 344–348. [CrossRef][PubMed]
    [Google Scholar]
  86. Vignuzzi M., Wendt E., Andino R.. ( 2008;). Engineering attenuated virus vaccines by controlling replication fidelity. . Nat Med 14:, 154–161. [CrossRef][PubMed]
    [Google Scholar]
  87. Zhou S., Liu R., Baroudy B. M., Malcolm B. A., Reyes G. R.. ( 2003;). The effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA. . Virology 310:, 333–342. [CrossRef][PubMed]
    [Google Scholar]
  88. Zuker M.. ( 2003;). Mfold web server for nucleic acid folding and hybridization prediction. . Nucleic Acids Res 31:, 3406–3415. [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.049171-0
Loading
/content/journal/jgv/10.1099/vir.0.049171-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error