Source: http://www.asmscience.org/content/book/10.1128/9781555816698.ch12
Timestamp: 2019-04-18 22:31:34+00:00

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Viral pathogenesis is not alien to the evolutionary history of a virus. Picornaviruses, simply by the fact of sharing a phylogenetic position, need not be associated with similar diseases, reflecting that the nature of the interactions with their host organisms may depend in a subtle manner on minimal genetic change of the virus. Picornaviruses have served to establish core concepts in the understanding of viruses as mutated collectivities and in establishing the relevance of quasispecies for viral pathogenesis. The adaptive potential of RNA viruses is also manifested in the response to selective agents administered to inhibit their replication. High mutation rates result in the almost-systematic selection of viral mutants resistant to antiviral inhibitors, either because resistant mutants are present in mutant spectra or because they are rapidly generated during viral replication. The participation of interfering genomes in virus extinction constitutes the basis of the lethal defection model of virus extinction by enhanced mutagenesis. The initial experiments to test the validity for RNA viruses of the error threshold concept consisted of documenting an adverse effect on viral infectivity as a result of increasing the mutation rate of poliovirus (PV) and vesicular stomatitis virus by chemical mutagens and base and nucleoside analogues added during viral RNA replication. Genetic modifications upon extensive passage of FMDV in BHK- 21 cells included genomes with internal in-frame deletions that were infectious by complementation in the absence of standard, wildtype genomes.
Molecular representation of the inhibitor of picornavirus replication, guanidine, and the standard nucleosides and mutagenic nucleoside analogs used in studies on lethal mutagenesis of FMDV described in this chapter.
1. Agudo, R.,, A. Arias, and, E. Domingo. 2009. 5-Fluorouracil in lethal mutagenesis of foot-and-mouth disease virus. Future Med. Chem. 1: 529– 539.
2. Agudo, R.,, A. Arias,, N. Pariente,, C. Perales,, C. Escarmis,, A. Jorge,, A. Marina, and, E. Domingo. 2008. Molecular characterization of a dual inhibitory and mutagenic activity of 5-fluorouridine triphosphate on viral RNA synthesis. Implications for lethal mutagenesis. J. Mol. Biol. 382: 652– 666.
3. Airaksinen, A.,, N. Pariente,, L. Menendez-Arias, and, E. Domingo. 2003. Curing of foot-and-mouth disease virus from persistently infected cells by ribavirin involves enhanced mutagenesis. Virology 311: 339– 349.
4. Anderson, J. P.,, R. Daifuku, and, L. A. Loeb. 2004. Viral error catastrophe by mutagenic nucleosides. Annu. Rev. Microbiol. 58: 183– 205.
5. Arias, A.,, J. J. Arnold,, M. Sierra,, E. D. Smidansky,, E. Domingo, and, C. E. Cameron. 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.
6. Arnold, J. J., and, C. E. Cameron. 2000. Poliovirus RNA-dependent RNA polymerase (3D pol). Assembly of stable, elongation-competent complexes by using a symmetrical primer-template substrate (sym/sub). J. Biol. Chem. 275: 5329– 5336.
7. Asahina, Y.,, N. Izumi,, N. Enomoto,, M. Uchihara,, M. Kurosaki,, Y. Onuki,, Y. Nishimura,, K. Ueda,, K. Tsuchiya,, H. Nakanishi,, T. Kitamura, and, S. Miyake. 2005. Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C. J. Hepatol. 43: 623– 629.
8. Baranowski, E.,, N. Sevilla,, N. Verdaguer,, C. M. Ruíz-Jarabo,, E. Beck, and, E. Domingo. 1998. Multiple virulence determinants of foot-and-mouth disease virus in cell culture. J. Virol. 72: 6362– 6372.
9. Batschelet, E.,, E. Domingo, and, C. Weissmann. 1976. The proportion of revertant and mutant phage in a growing population, as a function of mutation and growth rate. Gene 1: 27– 32.
10. Begue, J. P., and, D. Bonnet-Delpon. 2008. Bioorganic and Medicinal Chemistry of Fluorine. John Wiley & Sons, Inc., Hoboken, NJ.
11. Biron, C. A., and, G. C. Sen. 2007. Innate responses to viral infections, p. 249–278. In D. M. Knipe and, P. M. Howley (ed.), Fields Virology, 5th ed. Lippincott Williams & Wilkins, Philadelphia, PA.
12. Boege, U.,, D. Kobasa,, S. Onodera,, G. D. Parks,, A. C. Palmenberg, and, D. G. Scraba. 1991. Characterization of Mengo virus neutralization epitopes. Virology 181: 1– 13.
13. Boerlijst, M. C.,, S. Boenhoefer, and, M. A. Nowak. 1996. Viral quasispecies and recombination. Proc. R. Soc. Lond. B 263: 1577– 1584.
14. Bowen, D. G., and, C. M. Walker. 2005. The origin of quasispecies: cause or consequence of chronic hepatitis C viral infection? J. Hepatol. 42: 408– 417.
15. Braciale, T. J.,, Y. S. Hahn, and, D. R. Burton. 2007. The adaptive immune response to viruses, p. 279–235. In D. M. Knipe and, P. M. Howley (ed.), Fields Virology, 5th ed. Lippincott Williams & Wilkins, Philadelphia, PA.
16. Briones, C., and, E. Domingo. 2008. Minority report: hidden memory genomes in HIV-1 quasispecies and possible clinical implications. AIDS Rev. 10: 93– 109.
17. Bull, J. J.,, R. A. Sanjuán, and, C. O. Wilke. 2008. Lethal mutagenesis, p. 207–218. In E. Domingo,, C. Parrish, and, J. J. Holland (ed.), Origin and Evolution of Viruses. Elsevier, Amsterdam, The Netherlands.
18. Carrillo, C.,, Z. Lu,, M. V. Borca,, A. Vagnozzi,, G. F. Kutish, and, D. L. Rock. 2007. Genetic and phenotypic variation of foot-and-mouth disease virus during serial passages in a natural host. J. Virol. 81: 11341– 11351.
19. Carrillo, C.,, J. Plana,, R. Mascarella,, J. Bergada, and, F. Sobrino. 1990. Genetic and phenotypic variability during replication of foot-and-mouth disease virus in swine. Virology 179: 890– 892.
20. Castro, C.,, J. J. Arnold, and, C. E. Cameron. 2005. Incorporation fidelity of the viral RNA-dependent RNA polymerase: a kinetic, thermodynamic and structural perspective. Virus Res. 107: 141– 149.
21. Chao, L. 1990. Fitness of RNA virus decreased by Muller’s ratchet. Nature 348: 454– 455.
22. Chevaliez, S.,, R. Brillet,, E. Lazaro,, C. Hezode, and, J. M. Pawlotsky. 2007. Analysis of ribavirin mutagenicity in human hepatitis C virus infection. J. Virol. 81: 7732– 7741.
23. Ciurea, A.,, L. Hunziker,, M. M. Martinic,, A. Oxenius,, H. Hengartner, and, R. M. Zinkernagel. 2001. CD4 + T-cell-epitope escape mutant virus selected in vivo. Nat. Med. 7: 795– 800.
24. Ciurea, A.,, P. Klenerman,, L. Hunziker,, E. Horvath,, B. M. Senn,, A. F. Ochsenbein,, H. Hengartner, and, R. M. Zinkernagel. 2000. Viral persistence in vivo through selection of neutralizing antibody-escape variants. Proc. Natl. Acad. Sci. USA 97: 2749– 2754.
25. Contreras, A. M.,, Y. Hiasa,, W. He,, A. Terella,, E. V. Schmidt, and, R. T. Chung. 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.
26. Cristina, J., and, M. Costa-Mattioli. 2007. Genetic variability and molecular evolution of hepatitis A virus. Virus Res. 127: 151– 157.
27. Crotty, S.,, C. E. Cameron, and, R. Andino. 2001. RNA virus error catastrophe: direct molecular test by using ribavirin. Proc. Natl. Acad. Sci. USA 98: 6895– 6900.
28. Crotty, S.,, D. Maag,, J. J. Arnold,, W. Zhong,, J. Y. N. Lau,, Z. Hong,, R. Andino, and, C. E. Cameron. 2000. The broad-spectrum antiviral ribonucleotide, ribavirin, is an RNA virus mutagen. Nat. Med. 6: 1375– 1379.
29. Crowder, S., and, K. Kirkegaard. 2005. Trans-dominant inhibition of RNA viral replication can slow growth of drug-resistant viruses. Nat. Genet. 37: 701– 709.
30. Cuevas, J. M.,, F. Gonzalez-Candelas,, A. Moya, and, R. Sanjuan. 2009. Effect of ribavirin on the mutation rate and spectrum of hepatitis C virus in vivo. J. Virol. 83: 5760– 5764.
31. Day, C. W.,, D. F. Smee,, J. G. Julander,, V. F. Yamshchikov,, R. W. Sidwell, and, J. D. Morrey. 2005. Error-prone replication of West Nile virus caused by ribavirin. Antiviral Res. 67: 38– 45.
32. de la Torre, J. C.,, E. Wimmer, and, J. J. Holland. 1990. Very high frequency of reversion to guanidine resistance in clonal pools of guanidine-dependent type 1 poliovirus. J. Virol. 64: 664– 671.
33. Dixit, N. M.,, J. E. Layden-Almer,, T. J. Layden, and, A. S. Perelson. 2004. Modelling how ribavirin improves interferon response rates in hepatitis C virus infection. Nature 432: 922– 924.
34. Domingo, E. 2006. Quasispecies: Concepts and Implications for Virology. Springer Verlag, Berlin, Germany.
35. Domingo, E. 2007. Virus evolution, p. 389–421. In D. M. Knipe,, P. M. Howley,, D. E. Griffin,, R. A. Lamb,, M. A. Martin,, B. Roizman, and, S. E. Straus (ed.), Fields Virology, 5th ed. Lippincott Williams & Wilkins, Philadelphia, PA.
36. Domingo, E., and, J. Gomez. 2007. Quasispecies and its impact on viral hepatitis. Virus Res. 127: 131– 150.
37. Domingo, E.,, C. Gonzalez-Lopez,, N. Pariente,, A. Airaksinen, and, C. Escarmis. 2005. Population dynamics of RNA viruses: the essential contribution of mutant spectra. Arch. Virol. Suppl. 2005: 59– 71.
38. Domingo, E.,, J. J. Holland,, C. Biebricher, and, M. Eigen. 1995. Quasispecies: the concept and the word, p. 171–180. In A. Gibbs,, C. Calisher, and, F. García-Arenal (ed.), Molecular Evolution of the Viruses. Cambridge University Press, Cambridge, England.
39. Domingo, E.,, V. Martín,, C. Perales, and, C. Escarmís. 2008. Coxsackieviruses and quasispecies theory: evolution of enteroviruses. Curr. Top. Microbiol. Immunol. 323: 3– 32.
40. Domingo, E.,, C. Parrish, and, J. J. E. Holland. 2008. Origin and Evolution of Viruses, 2nd ed. Elsevier, Oxford, United Kingdom.
41. Domingo, E.,, D. Sabo,, T. Taniguchi, and, C. Weissmann. 1978. Nucleotide sequence heterogeneity of an RNA phage population. Cell 13: 735– 744.
42. Domingo, E., and, S. Wain-Hobson. 2009. The 30th anniversary of quasispecies. Meeting on quasispecies: past, present and future. EMBO Rep. 10: 444– 448.
43. Drake, J. W., and, J. J. Holland. 1999. Mutation rates among RNA viruses. Proc. Natl. Acad. Sci. USA 96: 13910– 13913.
44. Duarte, E.,, D. Clarke,, A. Moya,, E. Domingo, and, J. Holland. 1992. Rapid fitness losses in mammalian RNA virus clones due to Muller’s ratchet. Proc. Natl. Acad. Sci. USA 89: 6015– 6019.
45. Duarte, E. A.,, I. S. Novella,, S. Ledesma,, D. K. Clarke,, A. Moya,, S. F. Elena,, E. Domingo, and, J. J. Holland. 1994. Subclonal components of consensus fitness in an RNA virus clone. J. Virol. 68: 4295– 4301.
46. Eggers, H. J., and, I. Tamm. 1965. Coxsackie A9 virus: mutation from drug dependence to drug independence. Science 148: 97– 98.
47. Eigen, M. 2002. Error catastrophe and antiviral strategy. Proc. Natl. Acad. Sci. USA 99: 13374– 13376.
48. Eigen, M. 2000. Natural selection: a phase transition? Biophys. Chem. 85: 101– 123.
49. Eigen, M. 1996. On the nature of virus quasispecies. Trends Microbiol. 4: 216– 218.
50. Eigen, M. 1971. Self-organization of matter and the evolution of biological macromolecules. Naturwissenschaften 58: 465– 523.
51. Eigen, M., and, P. Schuster. 1979. The Hypercycle. A Principle of Natural Self-Organization. Springer, Berlin, Germany.
52. Emini, E. A.,, B. A. Jameson,, A. J. Lewis,, G. R. Larsen, and, E. Wimmer. 1982. Poliovirus neutralization epitopes: analysis and localization with neutralizing monoclonal antibodies. J. Virol. 43: 997– 1005.
53. Eriksson, N.,, L. Pachter,, Y. Mitsuya,, S. Y. Rhee,, C. Wang,, B. Gharizadeh,, M. Ronaghi,, R. W. Shafer, and, N. Beerenwinkel. 2008. Viral population estimation using pyrosequencing. PLoS Comput. Biol. 4: e1000074.
54. Escarmís, C.,, M. Dávila,, N. Charpentier,, A. Bracho,, A. Moya, and, E. Domingo. 1996. Genetic lesions associated with Muller’s ratchet in an RNA virus. J. Mol. Biol. 264: 255– 267.
55. Escarmís, C.,, E. Lazaro,, A. Arias, and, E. Domingo. 2008. Repeated bottleneck transfers can lead to non-cytocidal forms of a cytopathic virus: implications for viral extinction. J. Mol. Biol. 376: 367– 379.
56. Escarmís, C.,, E. Lázaro, and, S. C. Manrubia. 2006. Population bottlenecks in quasispecies dynamics. Curr. Top. Microbiol. Immunol. 299: 141– 170.
57. Escarmís, C.,, C. Perales, and, E. Domingo. 2009. Biological effect of Muller’s ratchet: distant capsid site can affect picorna-virus protein processing. J. Virol. 83: 6748– 6756.
58. Fauquet, C. M.,, M. A. Mayo,, J. Maniloff,, U. Desselberger, and, L. A. Ball (ed.). 2005. Virus Taxonomy. VIIIth Report of the International Committee on Taxonomy of Viruses. Elsevier Academic Press, San Diego, CA.
59. Ferrer-Orta, C.,, R. Agudo,, E. Domingo, and, N. Verdaguer. 2009. Structural insights into replication initiation and elongation processes by the FMDV RNA-dependent RNA polymerase. Curr. Opin. Struct. Biol. 19: 752– 758.
60. Ferrer-Orta, C.,, A. Arias,, R. Agudo,, R. Perez-Luque,, C. Escarmis,, E. Domingo, and, N. Verdaguer. 2006. The structure of a protein primer-polymerase complex in the initiation of genome replication. EMBO J. 25: 880– 888.
61. Ferrer-Orta, C.,, A. Arias,, R. Pérez-Luque,, C. Escarmís,, E. Domingo, and, N. Verdaguer. 2007. Sequential structures provide insights into the fidelity of RNA replication. Proc. Natl. Acad. Sci. USA 104: 9463– 9468.
62. Ferrer-Orta, C.,, A. Arias,, R. Perez-Luque,, C. Escarmis,, E. Domingo, and, N. Verdaguer. 2004. Structure of foot-and-mouth disease virus RNA-dependent RNA polymerase and its complex with a template-primer RNA. J. Biol. Chem. 279: 47212– 47221.
63. Ferrer-Orta, C.,, M. Sierra,, R. Agudo,, I. de la Higuera,, A. Arias,, R. Perez-Luque,, C. Escarmis,, E. Domingo, and, N. Verdaguer. 2010. Structure of foot-and-mouth disease virus mutant polymerases with reduced sensitivity to ribavirin. J. Virol. 84: 6188– 6199.
64. Figlerowicz, M.,, M. Alejska,, A. Kurzynska-Kokorniak, and, M. Figlerowicz. 2003. Genetic variability: the key problem in the prevention and therapy of RNA-based virus infections. Med. Res. Rev. 23: 488– 518.
65. García-Arriaza, J.,, S. C. Manrubia,, M. Toja,, E. Domingo, and, C. Escarmís. 2004. Evolutionary transition toward defective RNAs that are infectious by complementation. J. Virol. 78: 11678– 11685.
66. García-Arriaza, J.,, S. Ojosnegros,, M. Dávila,, E. Domingo, and, C. Escarmis. 2006. Dynamics of mutation and recombination in a replicating population of complementing, defective viral genomes. J. Mol. Biol. 360: 558– 572.
67. Gitlin, L.,, J. K. Stone, and, R. Andino. 2005. Poliovirus escape from RNA interference: short interfering RNA-target recognition and implications for therapeutic approaches. J. Virol. 79: 1027– 1035.
68. González-López, C.,, A. Arias,, N. Pariente,, G. Gómez-Mariano, and, E. Domingo. 2004. Preextinction viral RNA can interfere with infectivity. J. Virol. 78: 3319– 3324.
69. González-López, C.,, G. Gómez-Mariano,, C. Escarmís, and, E. Domingo. 2005. Invariant aphthovirus consensus nucleotide sequence in the transition to error catastrophe. Infect. Genet. Evol. 5: 366– 374.
70. Graci, J. D., and, C. E. Cameron. 2004. Challenges for the development of ribonucleoside analogues as inducers of error catastrophe. Antivir. Chem. Chemother. 15: 1– 13.
71. Graci, J. D., and, C. E. Cameron. 2008. Therapeutally targeting RNA viruses via lethal mutagenesis. Future Virol. 3: 553– 566.
72. Grande-Pérez, A.,, G. Gómez-Mariano,, P. R. Lowenstein, and, E. Domingo. 2005. Mutagenesis-induced, large fitness variations with an invariant arenavirus consensus genomic nucleotide sequence. J. Virol. 79: 10451– 10459.
73. Grande-Pérez, A.,, E. Lazaro,, P. Lowenstein,, E. Domingo, and, S. C. Manrubia. 2005. Suppression of viral infectivity through lethal defection. Proc. Natl. Acad. Sci. USA 102: 4448– 4452.
74. Heinz, B. A.,, R. R. Rueckert,, D. A. Shepard,, F. J. Dutko,, M. A. McKinlay,, M. Fancher,, M. G. Rossmann,, J. Badger, and, T. J. Smith. 1989. Genetic and molecular analyses of spontaneous mutants of human rhinovirus 14 that are resistant to an antiviral compound. J. Virol. 63: 2476– 2485.
75. Holland, J. 2006. Transitions in understanding of RNA viruses: a historical perspective. Curr. Top. Microbiol. Immunol. 299: 371– 401.
76. Holland, J. J.,, E. Domingo,, J. C. de la Torre, and, D. A. Steinhauer. 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.
77. Holland, J. J.,, K. Spindler,, F. Horodyski,, E. Grabau,, S. Nichol, and, S. VandePol. 1982. Rapid evolution of RNA genomes. Science 215: 1577– 1585.
78. Holmes, E. C. 2008. Comparative studies of RNA virus evolution, p. 119–134. In E. Domingo,, C. R. Parrish, and, J. J. Holland (ed.), Origin and Evolution of Viruses, 2nd ed. Elsevier, Oxford, United Kingdom.
79. Hong, Z. 2003. The role of ribavirin-induced mutagenesis in HCV therapy: a concept or a fact? Hepatology 38: 807– 810.
80. Iranzo, J., and, S. C. Manrubia. 2009. Stochastic extinction of viral infectivity through the action of defectors. Europhys. Lett. 85: 18001.
81. Koonin, E. V.,, Y. I. Wolf,, K. Nagasaki, and, V. V. Dolja. 2008. The Big Bang of picorna-like virus evolution antedates the radiation of eukaryotic supergroups. Nat. Rev. Microbiol. 6: 925– 939.
82. Lanford, R. E.,, D. Chavez,, B. Guerra,, J. Y. Lau,, Z. Hong,, K. M. Brasky, and, B. Beames. 2001. Ribavirin induces error-prone replication of GB virus B in primary tamarin hepatocytes. J. Virol. 75: 8074– 8081.
83. Lazaro, E.,, C. Escarmis,, J. Perez-Mercader,, S. C. Manrubia, and, E. Domingo. 2003. Resistance of virus to extinction on bottleneck passages: study of a decaying and fluctuating pattern of fitness loss. Proc. Natl. Acad. Sci. USA 100: 10830– 10835.
84. Longley, D. B.,, D. P. Harkin, and, P. G. Johnston. 2003. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3: 330– 338.
85. Lutchman, G.,, S. Danehower,, B. C. Song,, T. J. Liang,, J. H. Hoofnagle,, M. Thomson, and, M. G. Ghany. 2007. Mutation rate of the hepatitis C virus NS5B in patients undergoing treatment with ribavirin monotherapy. Gastroenterology 132: 1757– 1766.
86. Mainzer, K. 2009. Focus: complexity. Eur. Rev. 17: 219– 452.
87. Manrubia, S. C.,, C. Escarmis,, E. Domingo, and, E. Lazaro. 2005. High mutation rates, bottlenecks, and robustness of RNA viral quasispecies. Gene 347: 273– 282.
88. Mardis, E. R. 2008. The impact of next-generation sequencing technology on genetics. Trends Genet. 24: 133– 141.
89. Martin, V.,, A. Grande-Perez, and, E. Domingo. 2008. No evidence of selection for mutational robustness during lethal mutagenesis of lymphocytic choriomeningitis virus. Virology 378: 185– 192.
90. Mas, A.,, C. López-Galíndez,, I. Cacho,, J. Gómez, and, M. A. Martinez. 2010. Unfinished stories on viral quasispecies and Darwinian views of evolution. J. Mol. Biol. 397: 865– 877.
91. Mateu, M. G. 1995. Antibody recognition of picornaviruses and escape from neutralization: a structural view. Virus Res. 38: 1– 24.
92. Melnick, J. L.,, D. Crowther, and, J. Barrera-Oro. 1961. Rapid development of drug-resistant mutants of poliovirus. Science 134: 557.
93. Minor, P. D. 1990. Antigenic structure of picornaviruses. Curr. Top. Microbiol. Immunol. 161: 121– 154.
94. Minor, P. D. 1998. Picornaviruses, p. 485–510. In B. W. J. Mahy and, A. C. Collier (ed.), Topley and Wilson’s Microbiology and Microbial Infections, 9th ed., vol. I: Virology. Arnold, London, England.
95. Muñoz, E.,, J. M. Park, and, M. W. Deem. 2008. Quasispecies theory for horizontal gene transfer and recombination. Phys. Rev. E 78: 061921.
96. Ng, K. K.,, J. J. Arnold, and, C. E. Cameron. 2008. Structure-function relationships among RNA-dependent RNA polymerases. Curr. Top. Microbiol. Immunol. 320: 137– 156.
97. Nijhuis, M.,, N. M. van Maarseveen, and, C. A. Boucher. 2009. Antiviral resistance and impact on viral replication capacity: evolution of viruses under antiviral pressure occurs in three phases. Handb. Exp. Pharmacol. 2009: 299– 320.
98. Nowak, M. A., and, P. Schuster. 1989. Error thresholds of replication in finite populations mutation frequencies and the onset of Muller’s ratchet. J. Theor. Biol. 137: 375– 395.
99. Ojosnegros, S.,, N. Beerenwinkel,, T. Antal,, M. A. Nowak,, C. Escarmís, and, E. Domingo. 2010. Competition-colonization dynamics in an RNA virus. Proc. Natl. Acad. Sci. USA 107: 2108– 2112.
100. Page, K. M., and, M. A. Nowak. 2002. Unifying evolutionary dynamics. J. Theor. Biol. 219: 93– 98.
101. Pariente, N.,, A. Airaksinen, and, E. Domingo. 2003. Muta-genesis versus inhibition in the efficiency of extinction of foot-and-mouth disease virus. J. Virol. 77: 7131– 7138.
102. Perales, C.,, R. Agudo, and, E. Domingo. 2009. Counteracting quasispecies adaptability: extinction of a ribavirin-resistant virus mutant by an alternative mutagenic treatment. PLoS One 4: e5554.
103. Perales, C.,, R. Agudo,, H. Tejero,, S. C. Manrubia, and, E. Domingo. 2009. Benefits of sequential inhibitor-mutagen lethal mutagenesis treatments. PLoS Pathog. 5: e1000658.
104. Perales, C.,, R. Mateo,, M. G. Mateu, and, E. Domingo. 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.
105. Perelson, A. S., and, T. J. Layden. 2007. Ribavirin: is it a mutagen for hepatitis C virus? Gastroenterology 132: 2050– 2052.
106. Pfeiffer, J. K., and, K. Kirkegaard. 2006. Bottleneck-mediated quasispecies restriction during spread of an RNA virus from inoculation site to brain. Proc. Natl. Acad. Sci. USA 103: 5520– 5525.
107. Pfeiffer, J. K., and, K. Kirkegaard. 2005. Increased fidelity reduces poliovirus fitness under selective pressure in mice. PLoS Pathog. 1: 102– 110.
108. Pfeiffer, J. K., and, K. Kirkegaard. 2005. Ribavirin resistance in hepatitis C virus replicon-containing cell lines conferred by changes in the cell line or mutations in the replicon RNA. J. Virol. 79: 2346– 2355.
109. Pfeiffer, J. K., and, K. Kirkegaard. 2003. A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity. Proc. Natl. Acad. Sci. USA 100: 7289– 7294.
110. Prabhakar, B. S.,, V. M. Haspel,, P. R. McClintock, and, A. L. Notkins. 1982. High frequency of antigenic variants among naturally occurring human coxsackie B4 virus isolates identified by monoclonal antibodies. Nature 300: 374– 376.
111. Rodríguez-Calvo, T.,, S. Ojosnegros,, M. Sanz-Ramos,, J. García-Arriaza,, C. Escarmís,, E. Domingo, and, N. Sevilla. 2010. New vaccine design based on defective genomes that combines features of attenuated and inactivated vaccines. PLoS One 5 (4) : e10414.
112. Romero, J. R. 2008. Pediatric group B coxsackievirus infections. Curr. Top. Microbiol. Immunol. 323: 223– 239.
113. Ruiz-Jarabo, C. M.,, A. Arias,, E. Baranowski,, C. Escarmís, and, E. Domingo. 2000. Memory in viral quasispecies. J. Virol. 74: 3543– 3547.
114. Ruiz-Jarabo, C. M.,, A. Arias,, C. Molina-París,, C. Briones,, E. Baranowski,, C. Escarmís, and, E. Domingo. 2002. Duration and fitness dependence of quasispecies memory. J. Mol. Biol. 315: 285– 296.
115. Ruiz-Jarabo, C. M.,, C. Ly,, E. Domingo, and, J. C. de la Torre. 2003. Lethal mutagenesis of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). Virology 308: 37– 47.
116. Saakian, D. B., and, C. K. Hu. 2006. Exact solution of the Eigen model with general fitness functions and degradation rates. Proc. Natl. Acad. Sci. USA 103: 4935– 4939.
117. Sanz-Ramos, M.,, F. Diaz-San Segundo,, C. Escarmis,, E. Domingo, and, N. Sevilla. 2008. Hidden virulence determinants in a viral quasispecies in vivo. J. Virol. 82: 10465– 10476.
118. Severson, W. E.,, C. S. Schmaljohn,, A. Javadian, and, C. B. Jonsson. 2003. Ribavirin causes error catastrophe during Hantaan virus replication. J. Virol. 77: 481– 488.
119. Sherry, B.,, A. G. Mosser,, R. J. Colonno, and, R. R. Rueckert. 1986. Use of monoclonal antibodies to identify four neutralization immunogens on a common cold picornavirus, human rhinovirus 14. J. Virol. 57: 246– 257.
120. Sierra, M.,, A. Airaksinen,, C. González-López,, R. Agudo,, A. Arias, and, E. Domingo. 2007. Foot-and-mouth disease virus mutant with decreased sensitivity to ribavirin: implications for error catastrophe. J. Virol. 81: 2012– 2024.
121. Sierra, S.,, M. Dávila,, P. R. Lowenstein, and, E. Domingo. 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.
122. Solé, R., and, B. Goodwin. 2000. Signs of Life. How Complexity Pervades Biology. Basic Books, New York, NY.
123. Stapleton, J. T., and, S. M. Lemon. 1987. Neutralization escape mutants define a dominant immunogenic neutralization site on hepatitis A virus. J. Virol. 61: 491– 498.
124. Steitz, T. A., and, J. A. Steitz. 1993. A general two-metal-ion mechanism for catalytic RNA. Proc. Natl. Acad. Sci. USA 90: 6498– 6502.
125. Swetina, J., and, P. Schuster. 1982. Self-replication with errors. A model for polynucleotide replication. Biophys. Chem. 16: 329– 345.
126. Teotonio, H.,, I. M. Chelo,, M. Bradic,, M. R. Rose, and, A. D. Long. 2009. Experimental evolution reveals natural selection on standing genetic variation. Nat. Genet. 41: 251– 257.
127. Tracy, S.,, N. M. Chapman,, K. M. Drescher,, K. Kono, and, W. Tapprich. 2006. Evolution of virulence in picornaviruses. Curr. Top. Microbiol. Immunol. 299: 193– 209.
128. Tsibris, A. M.,, B. Korber,, R. Arnaout,, C. Russ,, C. C. Lo,, T. Leitner,, B. Gaschen,, J. Theiler,, R. Paredes,, Z. Su,, M. D. Hughes,, R. M. Gulick,, W. Greaves,, E. Coakley,, C. Flexner,, C. Nusbaum, and, D. R. Kuritzkes. 2009. Quantitative deep sequencing reveals dynamic HIV-1 escape and large population shifts during CCR5 antagonist therapy in vivo. PLoS One 4: e5683.
129. Vignuzzi, M.,, J. K. Stone,, J. J. Arnold,, C. E. Cameron, and, R. Andino. 2006. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature 439: 344– 348.
130. Vignuzzi, M.,, E. Wendt, and, R. Andino. 2008. Engineering attenuated virus vaccines by controlling replication fidelity. Nat. Med. 14: 154– 161.
131. Villaverde, A.,, E. Martínez-Salas, and, E. Domingo. 1988. 3D gene of foot-and-mouth disease virus. Conservation by convergence of average sequences. J. Mol. Biol. 204: 771– 776.
132. Vo, N. V.,, K. C. Young, and, M. M. C. Lai. 2003. Mutagenic and inhibitory effects of ribavirin on hepatitis C virus RNA polymerase. Biochemistry 42: 10462– 10471.
133. Wang, C.,, Y. Mitsuya,, B. Gharizadeh,, M. Ronaghi, and, R. W. Shafer. 2007. Characterization of mutation spectra with ultra-deep pyrosequencing: application to HIV-1 drug resistance. Genome Res. 17: 1195– 1201.
134. Webster, D. R.,, A. G. Hekele,, A. S. Lauring,, K. F. Fisher,, H. Li,, R. Andino, and, J. L. De Risi. 2009. An enhanced single base extension technique for the analysis of complex viral populations. PLoS ONE 4: e7453.
135. Wilke, C. O. 2005. Quasispecies theory in the context of population genetics. BMC Evol. Biol. 5: 44.
136. Wilke, C. O.,, C. Ronnewinkel, and, T. Martinetz. 2001. Dynamic fitness landscapes in molecular evolution. Physics Rep. 349: 395– 446.
137. Xie, Q.-C.,, D. McCahon,, J. R. Crowther,, G. J. Belsham, and, K. C. McCullough. 1987. Neutralization of foot-and-mouth disease virus can be mediated through any of at least three separate antigenic sites. J. Gen. Virol. 68: 1637– 1647.

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