Foot-and-Mouth Disease Virus Evolution: Exploring Pathways Towards Virus Extinction

  • E. Domingo
  • N. Pariente
  • A. Airaksinen
  • C. González-Lopez
  • S. Sierra
  • M. Herrera
  • A. Grande-Pérez
  • P. R. Lowenstein
  • S. C. Manrubia
  • E. Lázaro
  • C. Escarmís
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 288)


Foot-and-mouth disease virus (FMDV) is genetically and phenotypically variable. As a typical RNA virus, FMDV follows a quasispecies dynamics, with the many biological implications of such a dynamics. Mutant spectra provide a reservoir of FMDV variants, and minority subpopulations may become dominant in response to environmental demands or as a result of statistical fluctuations in population size. Accumulation of mutations in the FMDV genome occurs upon subjecting viral populations to repeated bottleneck events and upon viral replication in the presence of mutagenic base or nucleoside analogs. During serial bottleneck passages, FMDV survive during extended rounds of replication maintaining low average relative fitness, despite linear accumulation of mutations in the consensus genomic sequence. The critical event is the occurrence of a low frequency of compensatory mutations. In contrast, upon replication in the presence of mutagens, the complexity of mutant spectra increases, apparently no compensatory mutations can express their fitness-enhancing potential, and the virus can cross an error threshold for maintenance of genetic information, resulting in virus extinction. Low relative fitness and low viral load favor FMDV extinction in cell culture. The comparison of the molecular basis of resistance to extinction upon bottleneck passage and extinction by enhanced mutagenesis is providing new insights in the understanding of quasispecies dynamics. Such a comparison is contributing to the development of new antiviral strategies based on the transition of viral replication into error catastrophe.


Mutant Spectrum Error Threshold Compensatory Mutation Mutant Distribution Antiviral Strategy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Acharya R, Fry E, Stuart D, Fox G, Rowlands D, Brown F (1989) The three-dimensional structure of foot-and-mouth disease virus at 2.9 Å resolution. Nature 337:709–716CrossRefPubMedGoogle Scholar
  2. Airaksinen A, Pariente N, Menendez-Arias L, Domingo E (2003) Curing of foot-and-mouth disease virus from persistently infected cells by ribavirin involves enhanced mutagenesis. Virology 311:339–349CrossRefPubMedGoogle Scholar
  3. Alves D, Fontanari JF (1998) Error threshold in finite populations. Phys Rev E 57:7008–7013CrossRefGoogle Scholar
  4. Araki J, Matsubara H, Shimizu J, Mikane T, Mohri S, Mizuno J, Takaki M, Ohe T, Hirakawa M, Suga H (1999) Weibull distribution function for cardiac contraction: integrative analysis. Am J Physiol 277:H1940–H1945PubMedGoogle Scholar
  5. Arias A, Lázaro E, Escarmís C, Domingo E (2001) Molecular intermediates of fitness gain of an RNA virus: characterization of a mutant spectrum by biological and molecular cloning. J Gen Virol 82:1049–1060PubMedGoogle Scholar
  6. Arnold J, Hilton N (2003) Genome sequencing: revelations from a bread mould. Nature 422:821–822CrossRefPubMedGoogle Scholar
  7. Bachrach HL (1968) Foot-and-mouth disease virus. Annu Rev Microbiol 22:201–244CrossRefPubMedGoogle Scholar
  8. Baranowski E, Ruíz-Jarabo CM, Lim P, Domingo E (2001) Foot-and-mouth disease virus lacking the VP1 G-H loop: the mutant spectrum uncovers interactions among antigenic sites for fitness gain. Virology 288:192–202CrossRefPubMedGoogle Scholar
  9. Baranowski E, Ruíz-Jarabo CM, Pariente N, Verdaguer N, Domingo E (2003) Evolution of cell recognition by viruses: a source of biological novelty with medical implications. Adv Virus Res 62:19–111PubMedGoogle Scholar
  10. Bushman F (2002) Lateral DNA Transfer. Mechanisms and Consequences. Cold Spring Harbor, New York, Cold Spring Harbor Laboratory PressGoogle Scholar
  11. Chao L (1990) Fitness of RNA virus decreased by Muller's ratchet. Nature 348:454–455CrossRefPubMedGoogle Scholar
  12. Contreras AM, Hiasa Y, He W, Terella A, Schmidt EV, Chung RT (2002) Viral RNA mutations are region specific and increased by ribavirin in a full-length hepatitis C virus replication system. J Virol 76:8505–8517CrossRefPubMedGoogle Scholar
  13. Crotty S, Cameron CE, Andino R (2001) RNA virus error catastrophe: direct molecular test by using ribavirin. Proc Natl Acad Sci USA 98:6895–6900.CrossRefPubMedGoogle Scholar
  14. Crotty S, Maag D, Arnold JJ, Zhong W, Lau JYN, Hong Z, Andino R, Cameron CE (2000) The broad-spectrum antiviral ribonucleotide, ribavirin, is an RNA virus mutagen. Nat Med 6:1375–1379CrossRefPubMedGoogle Scholar
  15. de la Torre JC, Alarcón B, Martínez-Salas E, Carrasco L, Domingo E (1987) Ribavirin cures cells of a persistent infection with foot-and-mouth disease virus in vitro. J Virol 61:233–235PubMedGoogle Scholar
  16. Doel TR (2003) FMD vaccines. Virus Res 91:81–99CrossRefPubMedGoogle Scholar
  17. Domingo E, Ed. (2003) Microbe-host interaction: viruses. Curr Op Microbiol 6:4Google Scholar
  18. Domingo E, Baranowski E, Escarmís C, Sobrino F, Holland JJ (2002). Error frequencies of picornavirus RNA polymerases: evolutionary implications for viral populations Molecular Biology of Picornaviruses. Semler BL Wimmer E. Washington, DC, ASM: 285–298Google Scholar
  19. Domingo E, Biebricher C, Eigen M, Holland JJ (2001) Quasispecies and RNA Virus Evolution: Principles and Consequences. Austin, Landes BioscienceGoogle Scholar
  20. Domingo E, Escarmis C, Baranowski E, Ruiz-Jarabo CM, Carrillo E, Nunez JI, Sobrino F (2003) Evolution of foot-and-mouth disease virus. Virus Res 91:47–63CrossRefPubMedGoogle Scholar
  21. Domingo E, Sabo D, Taniguchi T, Weissmann C (1978) Nucleotide sequence heterogeneity of an RNA phage population. Cell 13:735–744CrossRefPubMedGoogle Scholar
  22. Domingo E, Verdaguer N, Ochoa WF, Ruiz-Jarabo CM, Sevilla N, Baranowski E, Mateu MG, Fita I (1999) Biochemical and structural studies with neutralizing antibodies raised against foot-and-mouth disease virus. Virus Res 62:169–175CrossRefPubMedGoogle Scholar
  23. Drake JW, Holland JJ (1999) Mutation rates among RNA viruses. Proc Natl Acad Sci USA 96:13910–13913CrossRefPubMedGoogle Scholar
  24. Duarte E, Clarke D, Moya A, Domingo E, Holland J (1992) Rapid fitness losses in mammalian RNA virus clones due to Muller's ratchet. Proc Natl Acad Sci USA 89:6015–6019PubMedGoogle Scholar
  25. Duarte EA, Novella IS, Ledesma S, Clarke DK, Moya A, Elena SF, Domingo E, Holland JJ (1994) Subclonal components of consensus fitness in an RNA virus clone. J Virol 68:4295–4301PubMedGoogle Scholar
  26. Eigen M (1971) Self-organization of matter and the evolution of biological macro-molecules. Naturwissenschaften 58:465–523CrossRefPubMedGoogle Scholar
  27. Eigen M (1996) On the nature of virus quasispecies. Trends Microbiol 4:216–218CrossRefPubMedGoogle Scholar
  28. Eigen M (2002) Error catastrophe and antiviral strategy. Proc Natl Acad Sci USA 99:13374–13376.CrossRefPubMedGoogle Scholar
  29. Eigen M, Biebricher CK (1988). Sequence space and quasispecies distribution. RNA Genetics. Domingo E, Ahlquist P Holland JJ. Boca Raton, FL., CRC Press. 3: 211–245Google Scholar
  30. Eigen M, Schuster P (1979) The hypercycle. A principle of natural self-organization. Berlin, SpringerGoogle Scholar
  31. 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 264:255–267CrossRefPubMedGoogle Scholar
  32. 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 285:495–505CrossRefPubMedGoogle Scholar
  33. Escarmís C, Gómez-Mariano G, Dávila M, Lázaro E, Domingo E (2002) Resistance to extinction of low fitness virus subjected to plaque-to-plaque transfers: diversification by mutation clustering. J Mol Biol 315:647–661.CrossRefPubMedGoogle Scholar
  34. Gell-Mann M (1994). Complex adaptive systems. Complexity Metaphors, models and reality. Cowan GA, Pines D Meltzer D. Reading, MA, Wesley Publishing Co.: 17–45Google Scholar
  35. Gibbs A, Calisher C, García-Arenal F, Eds. (1995) Molecular Basis of Virus Evolution. Cambridge, Cambridge University PressGoogle Scholar
  36. Graci JD, Cameron CE (2002) Quasispecies, error catastrophe, and the antiviral activity of ribavirin. Virology 298:175–180.CrossRefPubMedGoogle Scholar
  37. Grande-Pérez A, Sierra S, Castro MG, Domingo E, Lowenstein PR (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 USA 99:12938–12943.CrossRefPubMedGoogle Scholar
  38. Harris RS, Bishop KN, Sheehy AM, Craig HM, Petersen-Mahrt SK, Watt IN, Neuberger MS, Malim MH (2003) DNA deamination mediates innate immunity to retroviral infection. Cell 113:803–809CrossRefPubMedGoogle Scholar
  39. Holland J, Spindler K, Horodyski F, Grabau E, Nichol S, VandePol S (1982) Rapid evolution of RNA genomes. Science 215:1577–1585PubMedGoogle Scholar
  40. Holland JJ, Domingo E, de la Torre JC, Steinhauer DA (1990) Mutation frequencies at defined single codon sites in vesicular stomatitis virus and poliovirus can be increased only slightly by chemical mutagenesis. J Virol 64:3960–3962PubMedGoogle Scholar
  41. Ishihama A, Mizumoto K, Kawakami K, Kato A, Honda A (1986) Proofreading function associated with the RNA-dependent RNA polymerase from influenza virus. J Biol Chem 261:10417–10421PubMedGoogle Scholar
  42. Jackson T, King AM, Stuart DI, Fry E (2003) Structure and receptor binding. Virus Res 91:33–46CrossRefPubMedGoogle Scholar
  43. Kimata JT, Kuller L, Anderson DB, Dailey P, Overbaugh J (1999) Emerging cytopathic and antigenic simian immunodeficiency virus variants influence AIDS progression. Nat Med 5:535–541CrossRefPubMedGoogle Scholar
  44. Kinsey JA, Garrett-Engele PW, Cambareri EB, Selker EU (1994) The Neurospora transposon Tad is sensitive to repeat-induced point mutation (RIP). Genetics 138:657–664PubMedGoogle Scholar
  45. Lanford RE, Chavez D, Guerra B, Lau JY, Hong Z, Brasky KM, Beames B (2001) Ribavirin induces error-prone replication of GB virus B in primary tamarin hepatocytes. J Virol 75:8074–8081CrossRefPubMedGoogle Scholar
  46. Lázaro E, Escarmís C, Domingo E, Manrubia SC (2002) Modeling viral genome fitness evolution associated with serial bottleneck events: evidence of stationary states of fitness. J Virol 76:8675–8681.CrossRefPubMedGoogle Scholar
  47. Lázaro E, Escarmís C, Pérez-Mercader J, Manrubia SC, Domingo E (2003) Resistance of virus to extinction upon bottleneck passages: study of a decaying and fluctuating pattern of fitness loss. Proc Natl Acad Sci USA 100:10830–10835CrossRefPubMedGoogle Scholar
  48. Lecossier D, Bouchonnet F, Clavel F, Hance AJ (2003) Hypermutation of HIV-1 DNA in the absence of the Vif protein. Science 300:1112CrossRefPubMedGoogle Scholar
  49. Lee CH, Gilbertson DL, Novella IS, Huerta R, Domingo E, Holland JJ (1997) Negative effects of chemical mutagenesis on the adaptive behavior of vesicular stomatitis virus. J Virol 71:3636–3640PubMedGoogle Scholar
  50. Loeb LA, Essigmann JM, Kazazi F, Zhang J, Rose KD, Mullins JI (1999) Lethal mutagenesis of HIV with mutagenic nucleoside analogs. Proc Natl Acad Sci USA 96:1492–1497CrossRefPubMedGoogle Scholar
  51. Loeb LA, Mullins JI (2000) Lethal mutagenesis of HIV by mutagenic ribonucleoside analogs. AIDS Res Hum Retroviruses 13:1–3CrossRefGoogle Scholar
  52. Maag D, Castro C, Hong Z, Cameron CE (2001) Hepatitis C virus RNA-dependent RNA polymerase (NS5B) as a mediator of the antiviral activity of ribavirin. J Biol Chem 276:46094–46098CrossRefPubMedGoogle Scholar
  53. Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D (2003) Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 424:99–103CrossRefPubMedGoogle Scholar
  54. Manrubia SC, Lázaro E, Pérez-Mercader J, Escarmís C, Domingo E (2003) Fitness distributions in exponentially growing asexual populations. Phys Rev Lett 90:188101–188104CrossRefPubMedGoogle Scholar
  55. Mason PW, Grubman MJ, Baxt B (2003) Molecular basis of pathogenesis of FMDV. Virus Res 91:9–32CrossRefPubMedGoogle Scholar
  56. Mateu MG, Hernández J, Martínez MA, Feigelstock D, Lea S, Pérez JJ, Giralt E, Stuart D, Palma EL, Domingo E (1994) Antigenic heterogeneity of a foot-and-mouth disease virus serotype in the field is mediated by very limited sequence variation at several antigenic sites. J Virol 68:1407–1417PubMedGoogle Scholar
  57. Maynard-Smith J (1976) The Evolution of Sex. Cambridge, Cambridge University PressGoogle Scholar
  58. Menéndez-Arias L (2002) Molecular basis of fidelity of DNA synthesis and nucleotide specificity of retroviral reverse transcriptases. Prog Nucl Acid Res Mol Biol 71:91–147Google Scholar
  59. Menéndez-Arias L (2002) Targeting HIV: antiretroviral therapy and development of drug resistance. Trends Pharmacol Sc 23:381–388CrossRefGoogle Scholar
  60. Morse SS, Ed. (1993) Emerging viruses, Oxford, Oxford University PressGoogle Scholar
  61. Morse SS, Ed. (1994) The Evolutionary Biology of Viruses. New York, Raven PressGoogle Scholar
  62. Muller HJ (1964) The relation of recombination to mutational advance. Mut Res 1:2–9Google Scholar
  63. Nilsson M, Snoad N (2000) Error threshold for quasispecies in dynamics fitness landscapes. Phys Rev Lett 84:191–194CrossRefPubMedGoogle Scholar
  64. Novella IS, Duarte EA, Elena SF, Moya A, Domingo E, Holland JJ (1995) Exponential increases of RNA virus fitness during large population transmissions. Proc Natl Acad Sci USA 92:5841–5844PubMedGoogle Scholar
  65. Novella IS, Elena SF, Moya A, Domingo E, Holland JJ (1995) Size of genetic bottlenecks leading to virus fitness loss is determined by mean initial population fitness. J Virol 69:2869–2872PubMedGoogle Scholar
  66. Novella IS, Quer J, Domingo E, Holland JJ (1999) Exponential fitness gains of RNA virus populations are limited by bottleneck effects. J Virol 73:1668–1671PubMedGoogle Scholar
  67. Nowak M, Schuster P (1989) Error thresholds of replication in finite populations mutation frequencies and the onset of Muller's ratchet. J Theor Biol 137:375–395.PubMedGoogle Scholar
  68. Núñez JI, Baranowski E, Molina N, Ruiz-Jarabo CM, Sánchez C, Domingo E, Sobrino F (2001) A single amino acid substitution in nonstructural protein 3A can mediate adaptation of foot-and-mouth disease virus to the guinea pig. J Virol 75:3977–3983CrossRefPubMedGoogle Scholar
  69. Pariente N (2003). Base molecular y dinámica de la extinción del virus de la fiebre aftosa por combinación de un mutágeno e inhibidores. Ph. D. Thesis, Universidad Autónoma de Madrid.Google Scholar
  70. Pariente N, Sierra S, Lowenstein PR, Domingo E (2001) Efficient virus extinction by combinations of a mutagen and antiviral inhibitors. J Virol 75:9723–9730.CrossRefPubMedGoogle Scholar
  71. Pfeiffer JK, 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 USAGoogle Scholar
  72. Richman DD, Ed. (1996) Antiviral Drug Resistance. New York, John Wiley and Sons Inc.Google Scholar
  73. Ripley LS (1990) Frameshift mutation: determinants of specificity. Annu Rev Genetics 24:189–213CrossRefGoogle Scholar
  74. Rose MS, Gillis AM, Sheldon RS (1999) Evaluation of the bias in using the time to the first event when the inter-event intervals have a Weibull distribution. Stat Med 18:139–154CrossRefPubMedGoogle Scholar
  75. Ruíz-Jarabo CM, Arias A, Baranowski E, Escarmís C, Domingo E (2000) Memory in viral quasispecies. J Virol 74:3543–3547CrossRefPubMedGoogle Scholar
  76. Ruíz-Jarabo CM, Arias A, Molina-París C, Briones C, Baranowski E, Escarmís C, Domingo E (2002) Duration and fitness dependence of quasispecies memory. J Mol Biol 315:285–296CrossRefPubMedGoogle Scholar
  77. Ruiz-Jarabo CM, Ly C, Domingo E, Torre JC (2003) Lethal mutagenesis of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). Virology 308:37–47CrossRefPubMedGoogle Scholar
  78. Severson WE, Schmaljohn CS, Javadian A, Jonsson CB (2003) Ribavirin causes error catastrophe during Hantaan virus replication. J Virol 77:481–488CrossRefPubMedGoogle Scholar
  79. Sierra S, Dávila M, Lowenstein PR, 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 74:8316–8323CrossRefPubMedGoogle Scholar
  80. Snell NJ (2001) Ribavirin—current status of a broad spectrum antiviral agent. Expert Opin Pharmacother 2:1317–1324CrossRefPubMedGoogle Scholar
  81. Sutmoller P, Barteling SS, Olascoaga RC, Sumption KJ (2003) Control and eradication of foot-and-mouth disease. Virus Res 91:101–144CrossRefPubMedGoogle Scholar
  82. Swetina J, Schuster P (1982) Self-replication with errors. A model for polynucleotide replication. Biophys Chem 16:329–345CrossRefPubMedGoogle Scholar
  83. Weibull WJ (1951) A statistical distribution function of wide applicability. Appl Mech 18:293–297Google Scholar
  84. Yuste E, Sánchez-Palomino S, Casado C, Domingo E, López-Galíndez C (1999) Drastic fitness loss in human immunodeficiency virus type 1 upon serial bottleneck events. J Virol 73:2745–2751PubMedGoogle Scholar
  85. Zhang H, Yang B, Pomerantz RJ, Zhang C, Arunachalam SC, Gao L (2003) The cytidine deaminase CEM15 induces hypermutation in newly synthesized HIV-1 DNA. Nature 424:94–98CrossRefPubMedGoogle Scholar
  86. Zhang Y, Jamaluddin M, Wang S, Tian B, Garofalo RP, Casola A, Brasier AR (2003) Ribavirin treatment up-regulates antiviral gene expression via the interferon-stimulated response element in respiratory syncytial virus-infected epithelial cells. J Virol 77:5933–5947CrossRefPubMedGoogle Scholar
  87. Zhou S, Liu R, Baroudy BM, Malcolm BA, Reyes GR (2003) The effect of ribavirin and IMPDH inhibitors on hepatitis C virus subgenomic replicon RNA. Virology 310:333–342PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • E. Domingo
    • 1
  • N. Pariente
    • 1
  • A. Airaksinen
    • 1
  • C. González-Lopez
    • 1
  • S. Sierra
    • 1
  • M. Herrera
    • 1
  • A. Grande-Pérez
    • 1
  • P. R. Lowenstein
    • 2
  • S. C. Manrubia
    • 3
  • E. Lázaro
    • 3
  • C. Escarmís
    • 1
  1. 1.Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)Universidad Autónoma de Madrid, CantoblancoMadridSpain
  2. 2.Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine, David Geffler School of MedicineUCLALos AngelesUSA
  3. 3.Centro de Astrobiología (CSIC-INTA), Torrejón de ArdozMadridSpain

Personalised recommendations