Picornavirus Variation

  • Esteban Domingo
  • Cristina Escarmís
  • Encarnación Martínez-Salas
  • Ana M. Martín Hernández
  • Mauricio G. Mateu
  • Miguel A. Martínez
Part of the NATO ASI Series book series (NSSA, volume 240)


Variation of viruses has multiple theoretical and practical implications. Because mutations are stochastic events, the extensive variability of RNA viruses and retroviruses has manifested, perhaps more than ever before, the indetermination and unpredictability that may be inherent to biological phenomena. RNA virus populations do not have a precisely defined genome, but consist of indeterminate mixtures of related genomes termed viral quasispecies (Fig. 1), an application to viruses of a theoretical concept first proposed by M. Eigen and colleagues to describe replicons in early life on earth (Eigen and Schuster, 1979; Eigen and Biebricher, 1988; Domingo et al., 1993). Initially, the quasispecies concept was ignored by many virologists as being purely “theoretical”. However, as pointed out by Holland and colleagues (1992) in a recent volume which summarizes the state of the art in virus variation: “Quasispecies populations are not hypothetical abstractions. They exist in animals and humans infected by RNA viruses such as vesicular stomatitis virus, foot-and-mouth disease virus, poliovirus, human immunodeficiency virus, influenza viruses, etc.”. Obviously, if comparative nucleotide sequencing of genomes from one population is restricted to a few hundred nucleotides several “identical genomes” may be found for simple statistical reasons (Fig. 1). The mutual influence between theoretical studies on quasispecies and experimental molecular virology has been determinant in providing the basis of what has been termed “RNA genetics”, a number of distinctive features associated with the error-prone replication of RNA genomes (Holland et al., 1982, 1992). Here we review evidence that picornaviruses are generally variable and that their populations are best described as quasispecies. The basic principles that influence Picornavirus variability and evolution do not differ in any substantial way from the principles guiding variation of other RNA viruses and retroviruses. In spite of the extensive heterogeneity of the human immunodeficiency viruses (HIV) within and between infected individuals, a comparison of the studies carried out with HIV-1 with those for other RNA viruses (including picornaviruses) led Temin (1989) to conclude that HIV” is not unique but merely different”. We hope to persuade virologists that in addition to having important “theoretical” impact, quasispecies and Picornavirus variation are intimately linked to “practical” problems, notably the control of picornaviral disease.


Human Immunodeficiency Virus Persistent Infection Simian Immunodeficiency Virus Internal Ribosome Entry Site Oral Poliovirus Vaccine 
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., and Brown, F., 1989, The three-dimensional structure of foot-and-mouth disease virus at 2.9 Å resolution, Nature 337: 709–715.PubMedCrossRefGoogle Scholar
  2. Ackermann, W.W., and Kurtz, 1955, Observations concerning a pre-existing infection of HeLa cells with poliomyelitis virus, J. Exp. Med. 102: 555–565.PubMedCrossRefGoogle Scholar
  3. Ahmad, A.L.M., Dowsett, A.B., and Tyrrell, D.A.K., 1987, Studies of rhinovirus resistant to an antiviral chalcone, Antiviral res. 8: 27–39.PubMedCrossRefGoogle Scholar
  4. Andries, K., Dewindt, B., Snoeks, J., Wouters, L., Moereels, H., Lewi, P.J., and Janssen, P.A.J., 1990. Two groups of rhinoviruses revealed by a panel of antiviral compounds present sequence divergence and differential pathogenicity, J. Virol. 64: 1117–1123.PubMedGoogle Scholar
  5. Argos, P., 1988, A sequence motif in many polymerases, Nucleic Acids Res. 16: 9909–9916.PubMedCrossRefGoogle Scholar
  6. Argos, P., and Fuller, S.D., 1988, A model for the hepatitis B virus core protein: prediction of antigenic sites and relationships to RNA virus capsid proteins, EMBO J. 7: 819–824.PubMedGoogle Scholar
  7. Argos, P., Kamer, G., Nickiin, M.J.H., and Wimmer, E., 1984, Similarity in gene organization and homology between proteins of aminal picornaviruses and a plant comovirus suggest common ancestry of these virus families, Nucleic Acids Res. 12: 7251–7267.PubMedCrossRefGoogle Scholar
  8. Bachrach, H.L., 1968, Foot-and mouth disease virus, Annu. Rev. Microbiol. 22: 201–244.PubMedCrossRefGoogle Scholar
  9. Banner, L.R., and Lai, M.M.C., 1991, Random nature of Coronavirus RNA recombination in the absence of selection pressure, Virology 185: 441–445.PubMedCrossRefGoogle Scholar
  10. Batschelet, E., Domingo. E., and 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.PubMedCrossRefGoogle Scholar
  11. Beck, E., and Strohmaier, K., 1987, Subtyping of European foot-and-mouth disease virus strains by nucleotide sequence determination, J. Virol. 61:1621–1629.PubMedGoogle Scholar
  12. Benmansour, A.M., Brahimi, M., Tuffereau, C., Coulon, P., Lafay, F., and Flamand, A., 1992, Rapid sequence evolution of street rabies glycoprotein is related to the highly heterogeneous nature of the virus population, Virology 187: 33–45.PubMedCrossRefGoogle Scholar
  13. Bharucha, E.P., and Mondkar, V.P., 1972, Neurological complications of a new conjunctivitis, Lancet ii 970–971.CrossRefGoogle Scholar
  14. Boege, U., Kobasa, D., Onodera, S., Parks, G.D., Palmenberg, A.C., and Seraba, D.G., 1991, Characterization of Mengo virus neutralization epitopes, Virology 181: 1–13.PubMedCrossRefGoogle Scholar
  15. Borzakian, S., Couderc, T., Barbier, Y., Attal, G., Pelletier, I., and Colbère-Garapin, F., 1992, Persistent poliovirus infection: Establishment and maintenance involve distinct mechanisms, Virology 186: 398–408.PubMedCrossRefGoogle Scholar
  16. Brahic, M., Bureau, J.F., and McAllister, A., 1991, Genetic determinants of the demyelinating disease caused by Theiler’s virus, Microbial Pathogenesis 11: 77–84.PubMedCrossRefGoogle Scholar
  17. Brown, F., 1989, Towards a molecular vaccine for foot-and-mouth disease, in: “Molecular Aspects of Picornavirus Infection and Detection”, B.L. Semler, and E. Ehrenfeld, eds., American Society for Microbiology, Washington, D.C.Google Scholar
  18. Brown, E.A., Day, S.P., Jansen, R.W., and Lemon, S.M., 1991, The 5′ nontranslated region of hepatitis A virus RNA: Secondary structure and elements required for translation in vitro, J. Virol. 65: 5828–5838.PubMedGoogle Scholar
  19. Bruenn, J.A., 1991, Relationships among the positive strand and double-strand RNA viruses as viewed througt their RNA-dependent RNA polymerases, Nucleic Acids Res. 19: 217–226.PubMedCrossRefGoogle Scholar
  20. Burns, D.P.W., and Desrosiers, R.C., 1991, Selection of genetic variants of simian immunodeficiency virus in persistently infected rhesus monkeys, J. Virol. 65: 1843–1854.PubMedGoogle Scholar
  21. Campbell, A.M.G., Williams, E.R., and Pearce, J., 1969, Late motor neuron degeneration following poliomyelitis, Neurology 19: 1101–1106.PubMedCrossRefGoogle Scholar
  22. Cao, X., Bergmann, I.E., and Beck, E., 1991, Comparison of the 5′ and 3′ untranslated genomic regions of virulent and attenuated foot-and-mouth disease viruses (strains O1 Campos and C3 Resende), J. Gen. Virol. 72: 2821–2825.PubMedCrossRefGoogle Scholar
  23. Carp, R.I., 1981, Persistent infection of human lymphoblastoid cells with poliovirus and development of temperature sensitive mutants, Intervirology 15: 49–56.PubMedCrossRefGoogle Scholar
  24. Carrillo, C., Plana, J., Mascarella, R., Bergadá, J., and Sobrino, F., 1990, Genetic and phenotypic variability during replication of foot-and-mouth disease virus in swine, Virology 179: 890–892.PubMedCrossRefGoogle Scholar
  25. Chao, L., 1990, Fitness of RNA virus decreased by Muller’s ratchet, Nature 348: 454–455.PubMedCrossRefGoogle Scholar
  26. Clarke, B.E., Brown, A.L., Currey, K.M., Newton, S.E., Rowlands, D.J., and Carroll, A.R., 1987, Potential secondary and tertiary structure in the genomic RNA of foot-and-mouth disease virus, Nucleic Acids Res. 15: 7067–7079.PubMedCrossRefGoogle Scholar
  27. Clarke, D., Duarte, E., Moya, A., Elena, S.F., Domingo, E., and Holland, J.J., 1993, Genetic bottlenecks and population passages cause profound fitness differences in RNA viruses, J. Virol. in press.Google Scholar
  28. Clewley, J.P., Pullin, J.S.K., Avery, R.J., and Moore, N.F., 1983, Oligonucleotide fingerprinting of the RNA species obtained from six Drosophila C virus isolates, J. Gen. Virol. 64: 503–506.CrossRefGoogle Scholar
  29. Colbère-Garapin, F., Christodoulou, C., Crainic, R., and Pelletier, I., 1989, Persistent poliovirus infection of human neuroblastoma cells, Proc. Natl. Acad. Sci. Usa 86: 7590–7594.PubMedCrossRefGoogle Scholar
  30. Cole, C.N., and Baltimore, D., 1973, Defective interfering particles of poliovirus. II. Nature of the defect, J. Mol. Biol. 76: 325–343.PubMedCrossRefGoogle Scholar
  31. Cooney, M.K., Fox, J.P., and Kenny, G.E., 1982, Antigenic groupings of 90 rhinovirus serotypes, Infect. Immun. 37: 642–647.PubMedGoogle Scholar
  32. Costa Giomi, M.P., Bergmann, I.E., Scodeller, E.A., Augé de Mello, P., Gomes, I., and La Torre, J.L., 1984, Heterogeneity of the polyribocytidylic acid tract in aphthovirus: biochemical and biological studies of viruses carrying polyribocytidylic acis tracts of different lengths, J. Virol. 51: 799–805.PubMedGoogle Scholar
  33. Costa Giomi, M.P., Gomes, I., Tiraboschi, B., Augé de Mello, P., Bergmann, I.E., Scodeller, E.A., and La Torre, J.L., 1988, Heterogeneity of the poliribocytidylic acid tract in aphthovirus: changes in the size of the poly (C) of viruses recovered from persistently infected cattle, Virology 162: 58–64.PubMedCrossRefGoogle Scholar
  34. Dalakas, M.C., 1986, New neuromuscular symptoms in patients with old poliomyelitis: a three year follow-up study, Eur. Neurol. 25: 381–387.PubMedCrossRefGoogle Scholar
  35. de la Torre, J.C., Alarcón, B., Martínez-Salas, E., Carrasco, L., and Domingo, E., 1987, Ribavirin cures cells of a persistent infection with foot-and-mouth disease virus in vivo, J. Virol. 61: 233–235.PubMedGoogle Scholar
  36. de la Torre, J.C., Dávila, M., Sobrino, F., Ortín, J., and Domingo, E., 1985, Establishment of cell lines persistently infected with foot-and-mouth disease virus, Virology 145: 24–35.PubMedCrossRefGoogle Scholar
  37. de la Torre, J.C., De la Luna, S., Díez, J., and Domingo, E., 1989a, Resistance to foot-and-mouth disease virus mediated by trans-acting cellular products, J. Virol. 63: 2385–2387.PubMedGoogle Scholar
  38. de la Torre, J.C., Giachetti, C., Semler, B.L., and Holland, J.J., 1992, High frequency of single-base transitions and extreme frequency of precise multiple-base reversion mutations in poliovirus, Proc.Natl. Acad. Sci. USA 89: 2531–2535.PubMedCrossRefGoogle Scholar
  39. de la Torre, J.C., Martínez-Salas, E., Díez, J., and Domingo, E., 1989b, Extensive cell heterogeneity during a persistent infection with foot-and-mouth disease virus, J. Virol. 63: 59–63.PubMedGoogle Scholar
  40. de la Torre, J.C., Martínez-Salas, E., Díez, J., Villaverde, A., Gebauer, F., Rocha, E., Dávila, M., and Domingo, E., 1988, Coevolution of cells and viruses in a persistent infection foot-and-mouth disease virus in cell culture, J. Virol. 62: 2050–2058.PubMedGoogle Scholar
  41. de la Torre, J.C., Wimmer, E., and Holland, J.J., 1990, Very high frequency of reversion to guanidine resistance in clonal pools of guanidine-dependent type 1 poliovirus, J. Virol. 64:664–671.PubMedGoogle Scholar
  42. Diez, J., Dávila, M., Escarmís, C., Mateu, M.G., Domínguez, J., Pérez, J.J., Giralt, E., Melero, J.A., and Domingo, E., 1990a, Unique amino acid substitutions in the capsid proteins of foot-and-mouth disease virus from a persistent infection in cell culture, J. Virol. 64: 5519–5528.PubMedGoogle Scholar
  43. Diez, J., Hofner, M., Domingo, E., and Donaldson, A.I., 1990b, Foot-and-mouth disease virus strains isolated from persistently infected cell cultures are attenuated for mice and cattle, Virus Res. 18: 3–8.PubMedCrossRefGoogle Scholar
  44. Dinter, Z., Philipson, L., and Wesslen, T., 1959, Persistent foot-and-mouth disease infections of cells in tissue culture, Virology 8: 542–544.PubMedCrossRefGoogle Scholar
  45. Domingo, E., 1989, RNA virus evolution and the control of viral disease, Prog. Drug Res. 33:93–133.PubMedCrossRefGoogle Scholar
  46. Domingo, E., Dávila, M., and Ortín, J., 1980, Nucleotide sequence heterogeneity of the RNA from a natural population of foot-and-mouth disease virus, Gene 11: 333–346.PubMedCrossRefGoogle Scholar
  47. Domingo, E., Escarmis, C., Martínez, M.A., Martínez-Salas, E., and Mateu, M.G., 1992, Foot-and-mouth disease virus populations are quasispecies, Curr. Top. Microbiol. Immunol. 176: 33–47.PubMedCrossRefGoogle Scholar
  48. Domingo, E., Flavell, R.A., and Weissmann, C., 1976, In vitro site-directed mutagenesis: generation and properties of an infectious extracistronic mutant of bacteriophage Qß, Gene 1: 3–25.PubMedCrossRefGoogle Scholar
  49. Domingo, E., and Holland, J.J., 1988, High error rates, population equilibrium, and evolution of RNA replication systems, in: “RNA Genetics” vol. 3 “Variability of RNA Genomes”, E. Domingo, J.J. Holland, and P. Ahlquist, eds., CRC Press Inc. Florida.Google Scholar
  50. Domingo, E., and Holland, J.J., 1992, Complications of RNA heterogeneity for the engineering of virus vaccines and antiviral agents, in:“Genetic Engineering, Principles and Methods”, vol. 14. J.K. Setlow, ed., Plenum Press, New York.Google Scholar
  51. Domingo, E., and Holland, J.J., 1993, Mutation rates and rapid evolution of RNA viruses, in: “Evolutionary Biology of Viruses”, S.S. Morse, ed., Raven Press, New York, in press.Google Scholar
  52. Domingo, E., Holland, J.J., Biebricher, C., and Eigen, M., 1993, Quasispecies: the concept and the word, in: “Molecular Evolution of Viruses”, A. Gibbs, C. Calisher and F. García-Arenal, eds., Cambridge University Press, in press.Google Scholar
  53. Domingo, E., Martínez-Salas, E., Sobrino, F., de la Torre, J.C., Portela, A., Ortin, J., López-Galíndez, C., Pérez-Breña, P., Villanueva, N., Nájera, R., VandePol, S., Steinhauer, D., DePolo, N., and Holland, J.J., 1985, The quasispecies (extremely heterogeneous) nature of viral RNA genome populations: biological relevance — a review, Gene 40: 1–8.PubMedCrossRefGoogle Scholar
  54. Domingo, E., Mateu, M.G., Martínez, M.A., Dopazo, J., Moya, A., and Sobrimo, F., 1990, Genetic variability and antigenic diversity of foot-and-mouth disease virus, in: “Applied Virology Research” vol. 2 “Virus Variation, Epidemiology and Control”, E. Kurstak, R.G. Marusyk, F.A. Murphy, and M.H.V. Van Regenmortel, eds. Plenum Publishing Co., New York.Google Scholar
  55. Domingo, E., Sabo, D., Taniguchi, T., and Weissmann, C., 1978, Nucleotide sequence heterogeneity of an RNA phage population, Cell 13: 735–744.PubMedCrossRefGoogle Scholar
  56. Dopazo, J., Sobrino, F., Palma, E.L., Domingo, E., and Moya, A., 1988, Gene encoding capsid protein VP1 of foot-and-mouth disease virus: a quasispecies model of molecular evolution, Proc. Natl. Acad. Sci. USA 85: 6811–68915.PubMedCrossRefGoogle Scholar
  57. Duarte, E., Clarke, D., Moya, A., Domingo, E., and Holland, J.J., 1992, Rapid fitness losses in mammalian RNA virus clones due to Muller’s ratchet, Proc. Natl. Acad. Sci. USA 89: 6015–6019.PubMedCrossRefGoogle Scholar
  58. Duke, G.M., Osorio, J.E., and Palmenberg, A.C., 1990, Attenuation of Mengo virus through genetic engineering of the 5′ noncoding poly (C) tract, Nature 343: 474–476.PubMedCrossRefGoogle Scholar
  59. Dunn, G., Begg, N.T., Cammack, N., and Minor, P.D., 1990, Virus excretion and mutation by infants following primary vaccination with live oral poliovaccine from two sources, J. Med. Virol. 32: 92–95.PubMedCrossRefGoogle Scholar
  60. Eggers, H.J., and Tamm, I., 1965, Coxsackie A9 virus: mutation from drug dependence to drug resistance, Science 148: 97–98.PubMedCrossRefGoogle Scholar
  61. Eigen, M., and Biebricher, C., 1988, Sequence space and quasispecies distribution, in: “RNA Genetics” vol. 3, E. Domingo, J.J. Holland, and P. Ahlquist, eds. CRC Press Inc. Boca Raton, Florida.Google Scholar
  62. Eigen, M., and Schuster, P., 1979, The Hypercycle. A Principle of Natural Self-Organization, Springer-Verlag, Berlin.Google Scholar
  63. Emini, E. A., Jameson, B.A., Lewis, A.J., Larsen G.R., and Wimmer, E., 1982, Poliovirus neutralization epitopes: Analysis and localization with neutralizing monoclonal antibodies, J. Virol. 43: 997–1005.PubMedGoogle Scholar
  64. Escarmís, C., Toja, M., Medina, M., and Domingo, E., 1992, Modifications of the 5′ untranslated region of foot-and-mouth disease virus after prolonged persistence in cell culture, Virus Res. in press.Google Scholar
  65. Evans, D.M.A., Dunn, G., Minor, P.D., Schild, G.D., Cann, A.J., Stanway, G., Almond, J.W., Currey, K., and Maizel, J.V., Jr, 1985, A single nucleotide change in the 5′ non-coding region of the genome of the Sabin type 3, poliovaccine is associated with increased neurovirulence, Nature 314: 548–550.PubMedCrossRefGoogle Scholar
  66. Felsestein, J., 1985, Confidence limits on phylogenies: an approach using the bootstrap, Evolution 39: 783–791.CrossRefGoogle Scholar
  67. Franssen, H., Leunissen, J., Goldbach, R., Lomonosoff, G., and Zimmern, D., 1984, Homologous sequences in non-structural proteins from cowpea mosaic virus and picornaviruses, EMBO J. 3: 855–861.PubMedGoogle Scholar
  68. Fuller, S.D., and Argos, P., 1987, Is Sindbis a simple Picornavirus with an envelope? EMBO J. 6: 1099–1105.PubMedGoogle Scholar
  69. Gauss-Müller, V., and Deinhardt, F., 1984, Effect of hepatitis A virus infection on cell metabolism in vitro, Proc. Soc. Exp. Biol. Med. 175: 10–15.PubMedGoogle Scholar
  70. Gebauer, F., de la Torre, J.C., Gomes, I., Mateu, M.G., Barahona, H., Tiraboschi, B., Bermann, I., Auge de Mello, P., and Domingo, E., 1988, Rapid selection of genetic and antigenic variants of foot-and-mouth disease virus during persistence in cattle, J. Virol. 62: 2041–2049.PubMedGoogle Scholar
  71. Gercel, C., Mahan, K.B., and Hamparian, V.V., 1985, Preliminary characterization of a persistent infection of HeLa cells with human rhinovirus type 2, J. Gen. Virol. 66: 131–139.PubMedCrossRefGoogle Scholar
  72. Gibson, J.P., and Righthand, V.F., 1985, Persistence of echovirus 6 in cloned human cells, J. Virol. 54: 219–223.PubMedGoogle Scholar
  73. González, M.J., Sáiz, J.C., Laor, O., and Moore, D.M., 1991, Antigenic stability of foot-and-mouth disease virus variants on serial passage in cell culture, J. Virol. 65: 3949–3953.PubMedGoogle Scholar
  74. Gorbalenya, A.E., and Koonin, E.V., 1989, Viral proteins containing the purine NTP-binding sequence pattern, Nucleic Acids Res. 17: 8413–8440.PubMedCrossRefGoogle Scholar
  75. Grant, R.A., Filman, D.J., Fujinami, R.S., Icenogle, J.P., and Hogle, J. M., 1992, Three-dimensional structure of Theiler virus, Proc. Natl. Acad. Sci. USA 89: 2061–2065.PubMedCrossRefGoogle Scholar
  76. Hahn, B.H., Shaw, G.M., Taylor, M.E., Redfield, R.R., Markham, P.D., Salahudin, S.Z., Wong-Staal, F., Gallo, R.C., Parks, E.S., and Parks, W.P., 1986, Genetic variation in HTLV-III/LAV over time in patients with AIDS or at risk for AIDS, Science 232: 1548–1553.PubMedCrossRefGoogle Scholar
  77. Halstead, S.B., 1980, Immunological parameters of Togavirus disease syndromes, in: “The Togaviruses. Biology, Structure, Replication”, R.W. Schlesinger, ed., Academic Press, New York.Google Scholar
  78. Haseloff, J., Goelet, P., Zimmern, D., Ahlquist, P., Dasgupta, R., and Kaesberg, P., 1984, Striking similarities in amino acid sequence among nonstructural proteins encoded by RNA viruses that have dissimilar genomic organization, Proc. Natl. Acad. Sci. USA 81:4358–4362.PubMedCrossRefGoogle Scholar
  79. Heinz, B.A., Rueckert, R.R., Shepard, D.A., Dutko, F.J., McKinlay, M.A., Francher, M., Rossmann, M.G., Badger, J., and Smith, T.J., 1989, Genetic and molecular analyses of spontaneous mutants of human rhinovirus 14 that are resistant to an antiviral compound, J. Virol. 63: 2476–2485.PubMedGoogle Scholar
  80. Hernández, J., Martínez, M.A., Rocha, E., Domingo, E., and Mateu, M.G., 1992, Generation of a subtype-specific neutralization epitope in foot-and-mouth disease virus of a different subtype, J. Gen. Virol. 73: 213–216.PubMedCrossRefGoogle Scholar
  81. Hogle, J.M., Chow, M., and Filman, D.J., 1985, Three-dimensional structure of poliovirus at 2.9 Å resolution, Science, 229: 1358–1365.PubMedCrossRefGoogle Scholar
  82. Holland, J.J., de la Torre, J.C., and Steinhauer, D.A., 1992, RNA virus populations as quasispecies, Curr Top. Microbiol. Immunol. 176: 1–20.PubMedCrossRefGoogle Scholar
  83. Holland, J.J., de la Torre, J.C., Clarke, D.K., and Duarte, E., 1991, Quantification of relative fitness and great adaptability of clonal populations of RNA viruses, J. Virol. 65:2960–2967.PubMedGoogle Scholar
  84. Holland, J.J., de la Torre, J.C., Steinhauer, D.A., Clarke, D., Duarte, E., and Domingo, E., 1989, Virus mutation frequencies can be greatly underestimated by monoclonal antibody neutralization of virions, J. Virol., 63: 5030–5036.PubMedGoogle Scholar
  85. Holland, J.J., Domingo, E., de la Torre, J.C., and 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.PubMedGoogle Scholar
  86. Holland, J.J., Spindler, K., Horodyski, F., Grabau, E., Nichol, S., and VandePol, 1982, Rapid evolution of RNA genomes, Science 215: 1577–1585.PubMedCrossRefGoogle Scholar
  87. Hollinger, F.B., and Ticehurst, J., 1990, Hepatitis A virus, in:“Virology”, B. N. Fields, D.M. Knipe et al., eds., Raven Press, New York.Google Scholar
  88. Hovi, T., Cantell, K., Huovilainen, A., Kinnunen, L., Kunonen, T., Lapinleimu, K., Pöyry, T., Roivaianen, M., Salama, N., Stenvik, M., Silander, A., Tholen, C.J., Salminen, S., and Weckstrom, P., 1986. Outbreak of paralytic poliomyelitis in Finland: widespread circulation of antigenically altered poliovirus type 3 in a vaccinated population, Lancet i: 1427–1432.CrossRefGoogle Scholar
  89. Jameson, B.A., Bonin, J., Wimmer, E., and Kew, O.M., 1985, Natural variants of the Sabin type 1 vaccine strain of poliovirus, and correlation with a poliovirus neutralization site, Virology 143: 337–341.PubMedCrossRefGoogle Scholar
  90. Johnson, R.T., 1982, Viral Infections of the Nervous System, Raven Press, New York.Google Scholar
  91. Kamahora, T., Itagaki, A., Hattori, N., Tsuchie, H., and Kurimura, T., 1985, Oligonucleotide fingerprint analysis of coxsackievirus A10 isolated in Japan, J. Gen. Virol. 66: 2627–2634.PubMedCrossRefGoogle Scholar
  92. Kamer, G., and Argos, P., 1984, Primary structural comparison od RNA-dependent polymerases from plant, animal and bacterial viruses, Nucleic Acids Res. 12: 7269–7282.PubMedCrossRefGoogle Scholar
  93. Kaplan, G., Levy, A., and Racaniello, V.R., 1989, Isolation and characterization of HeLa cell lines blocked at different steps in the poliovirus life cycle, J. Virol. 63: 43–51.PubMedGoogle Scholar
  94. Kew, O.M., and Nottay, B.K., 1984, Evolution of oral poliovirus vaccine strain in humans occurs by both mutation and intermolecular recombination, in: “Modern Approaches to Vaccines”, R. Chanock and R. Lerner, eds., Cold Spring Harbor, New York.Google Scholar
  95. Kew, O.M., Nottay, B.K., Hatch, M.N., Nakano, J.H., and Obijeski, J.F., 1981, Multiple genetic changes can occur in the oral poliovaccines upon replication in Humans, J. Gen. Virol. 56: 337–347.PubMedCrossRefGoogle Scholar
  96. Kew, O.M., Nottay, B.K., Rico-Hesse, R., and Pallansch, M.A., 1990, Molecular epidemiology of wild poliovirus transmission, in: “Applied Virology Research” vol. 2 “Virus Variability, Epidemiology and Control”, E. Kurstak, R.G. Marusyk, F.A. Murphy, and M.H.V. Van Regenmortel, eds., Plenum Publishing Co., New York.Google Scholar
  97. King, A.M.Q., 1988a, Recombination in positive strand RNA viruses, in: “RNA Gentics” vol. 2, E. Domingo, J.J. Holland, and P. Ahlquist, eds. CRC Press Inc., Boca Ratón, Florida.Google Scholar
  98. King, A.M.Q., 1988b, Preferred sites of recombination in poliovirus RNA: an analysis of 40 intertypic crossover sequences. Nucleic Acid Res. 16: 11705–11723.PubMedCrossRefGoogle Scholar
  99. Kinnunen, L., Pöyry, T., and Hovi, T., 1991, Generation of virus genetic lineages during an outbreak of poliomyelitis, J. Gen. Virol. 72: 2483–2489.PubMedCrossRefGoogle Scholar
  100. Kinnunen, L., Pöyry, T., and Hovi, T., 1992, Genetic diversity and rapid evolution of poliovirus in human hosts, Curr. Top. Microbiol. Immunol. 176: 49–61.PubMedCrossRefGoogle Scholar
  101. Kirkegaard, K., and Baltimore, D., 1986, The mechanism of RNA recombination in poliovirus, Cell 47: 433–443.PubMedCrossRefGoogle Scholar
  102. Kono, R., Uchida, Y., Sasagawa, A., Akao, Y., Kodama, H., Mukoyama, J., and Fujiwara, T., 1973, Neurovirulence of acute haemorrhagic conjunctivitis virus in monkeys, Lancet i: 61–63.CrossRefGoogle Scholar
  103. Koonin, E.V., 1991, The phylogeny of RNA-dependent RNA polymerases of positive-strand RNA viruses, J. Gen. Virol. 72: 2197–2206.PubMedCrossRefGoogle Scholar
  104. Koonin, E., Boyko, V.P., and Dolja, V.V., 1991, Small cysteine-rich proteins of different groups of plant RNA viruses are related to different families of nucleic acid-binding proteins, Virology 181: 395–398.PubMedCrossRefGoogle Scholar
  105. Krebs, O., and Marquardt, O., 1992, Identification and characterization of foot-and-mouth disease virus O1 Burgwedel/1987 as an intertypic recombinant, J. Gen. Virol. 73: 613–619.PubMedCrossRefGoogle Scholar
  106. Kuge, S., Kawamura, N., and Nomoto, A., 1989, Strong inclination toward transition mutation in nucleotide substitutions by poliovirus replicase, J. Mol. Biol. 207: 175–182.PubMedCrossRefGoogle Scholar
  107. Lai, M.M.C., 1992, Genetic recombination in RNA viruses, Curr. Top. Microbiol. Immunol. 176: 21–32.PubMedCrossRefGoogle Scholar
  108. Lemon, S.M., and Binn, L.N., 1983, Antigenic relatedness of two strains of hepatitis A virus determined by cross-neutralization, Infect. Immun. 42: 418–420.PubMedGoogle Scholar
  109. Lemon, S.M., Chao, S.-F., Jansen, R.W., Binn, L.N., and LeDuc, J.W., 1987, Genomic heterogeneity among human and nonhuman strains of hepatitis A virus, J. Virol. 61: 735–742.PubMedGoogle Scholar
  110. Lemon, S.M., and Ping, L.-H., 1989, Antigenic structure of hepatitis A virus, in: “Molecular Aspects of Picornavirus Infection and Detection”, B.L. Semler and E. Ehrenfeld, eds., American Society for Microbiology, Washington, D.C.Google Scholar
  111. Luo, M., He, C., Toth, K.S., Zhang, C.X., and Lipton, H.L., 1992, Three-dimensional structure of Theiler murine encephalomyelitis virus (Be An strain), Proc. Natl. Acad. Sci. USA 89: 2409–2413PubMedCrossRefGoogle Scholar
  112. Macadam, A.J., Arnold, C., Howlett, J., John, A., Marsden, S., Taffs, F., Reeve, P., Harnada, N., Wareham, K., Almond, J., Cammack, N., and Minor, P.D., 1989, Reversion of the attenuated and temperature-sensitive phenotypes of the Sabin type 3 strain of poliovirus in vaccinees, Virology 172: 408–414.PubMedCrossRefGoogle Scholar
  113. Martínez, M.A., Carrillo, C., González-Candelas, F., Moya, A., Domingo, E., and Sobrino, F., 1991a, Fitness alteration of foot-and-mouth disease virus mutants: measurement of adaptability of viral quasispecies. J. Virol. 65: 3954–3957.PubMedGoogle Scholar
  114. Martínez, M.A., Dopazo, J., Hernández, J., Mateu, M.G., Sobrino, F., Domingo, E., and Knowles, N.J., 1992, Evolution of the capsid protein genes of foot-and-mouth disease virus: antigenic variation without accumulation of amino acid substitutions over six decades, J. Virol. 66: 3557–3565.PubMedGoogle Scholar
  115. Martínez, M.A., Hernández, J. Piccone, M.E., Palma, E., L., Domingo, E., Knowles, N., and Mateu, M.G., 1991b, Two mechanisms of antigenic diversification of foot-and-mouth disease virus, Virology 184: 695–706.PubMedCrossRefGoogle Scholar
  116. Mateu, M.G., Andreu, D., Carreño, C., Roig, X., Cairo, J.J., Camarero, J.A., Giralt, E., and Domingo, E., 1992, Non-additive effects of multiple amino acid substitutions on antigen-antibody recognition, Eur. J. Immunol. 22: 1385–1389.PubMedCrossRefGoogle Scholar
  117. Mateu, M.G., Martínez, M.A., Capucci, L., Andreu, D., Giralt, E., Sobrino, F., Brocchi, E., and Domingo, E., 1990, A single amino acid substitution affects multiple overlapping epitopes in the major antigenic site of foot-and-mouth disease virus of serotype C, J. Gen. Virol., 71: 629–637.PubMedCrossRefGoogle Scholar
  118. Mateu, M.G., Martínez, M.A., Rocha, E., Andreu, D., Parejo, J., Giralt, E., Sobrino, F., and Domingo, E., 1989, Implications of a quasispecies genome structure: effects of frequent, naturally occurring amino acid substitutions on the antigenicity of foot-and-mouth disease virus, Proc. Natl. Acad. Sci. USA 86: 5883–5887.PubMedCrossRefGoogle Scholar
  119. McClure, M.A., Holland, J.J., and Perrault, J., 1980, Generation of defective interfering particles in picornaviruses, Virology 100: 408–418.PubMedCrossRefGoogle Scholar
  120. Meyers, G., Tautz, N., Dubovi, E.J., and Thiel, H-J., 1991, Viral cytopathogenicity correlated with integration of ubiquitincoding sequences, Virology 180: 602–616.PubMedCrossRefGoogle Scholar
  121. Minor, P.D., 1989, Humoral immune response to poliovirus, in: “Immune Responses, Virus Infections and Disease” N.J. Dimmock and P.D. Minor, eds., Society for General Microbiology, IRL Press, Oxford.Google Scholar
  122. Minor, P.D., 1990, Antigenic structure of picornaviruses, Curr. Top. Microbiol. Immunol. 161:121–154.PubMedCrossRefGoogle Scholar
  123. Minor, P.D., Dunn, G., Evans, D.M.A., Magrath, D.I., John, A., Howlett, J., Phillips. A., Westrop, G., Wareham, K., Almond, J.W., and Hogle, J.M., 1989, The temperature sensitivity of the sabin type 3 vaccine strain of poliovirus: molecular and structural effects of a mutation in the capsid protein VP3, J. Gen. Virol. 70: 1117–1123.PubMedCrossRefGoogle Scholar
  124. Minor, P.D., Ferguson, M., Evans, D.M.A., Almond, J.W., and Icenogle, J.P., 1986a, Antigenic structure of polioviruses of serotypes 1, 2 and 3, J. Gen. Virol. 67: 1283–1291.PubMedCrossRefGoogle Scholar
  125. Minor, P.D., John, A., Ferguson, M., and Icenogle, J.P., 1986b, Antigenic and molecular evolution of the vaccine strain of type 3 poliovirus during the period of excretion by a primary vaccinee, J. Gen. Virol. 67: 693–706.PubMedCrossRefGoogle Scholar
  126. Minor, P.D., Schild, G.C., Bootman, J., Evans, D.M.A., Ferguson, M., Reeve, P., Spitz, M., Stanway, F., Cann, A.J., Hauptmann, R., Clarke, L-D., Mountfort, R.C., and Almond, J.W., 1983, Location and primary structure of a major antigenic site for poliovirus neutralization, Nature 301: 674–679.PubMedCrossRefGoogle Scholar
  127. Monroe, S.S., and Schlesinger, S., 1983, RNAs from two independently isolated defective interfering particles of Sindbis virus contain cellular tRNA sequences at their 5′ends, Proc. Natl. Acad. Sci. USA 80: 3279–3283.PubMedCrossRefGoogle Scholar
  128. Mulder, D.W., Rosenbaum, R.A., and Layton, D.D., 1972, Late progression of poliomyelitis or forme fruste amyotrophic lateral sclerosis, Mayo Clin. Proc. 47: 756–761.PubMedGoogle Scholar
  129. Nomoto, A., Jacobson, A., Lee, Y.F., Dunn, J., and Wimmer, E., 1979, Defective interfering particles of poliovirus: mapping of deletions and evidence that the deletions in the genomes of DI (1), (2) and (3) are located in the same region, J. Mol. Biol. 128: 179–196.PubMedCrossRefGoogle Scholar
  130. Nottay, B.K., Kew, O.M., Hatch, M.H., Heyward, J.T., and Obijeski, J.F., 1981, Molecular variation of type 1 vaccine-related and wild poliovirus during replication in humans, Virology 108: 405–423.PubMedCrossRefGoogle Scholar
  131. Nowak, M.A., Anderson, R.M., McLean, A.R., Wolfs, T.F.W., Goudsmits, J., and May, R.M., 1991, Antigenic diversity thresholds and the development of AIDS, Science 254: 963–969.PubMedCrossRefGoogle Scholar
  132. Nuesch, J., Krech, S., and Siegl, G., 1988, Detection and characterization of subgenomic RNAs in hepatitis A virus particles, Virology 165: 419–427.PubMedCrossRefGoogle Scholar
  133. Palmenberg, A., 1989, Sequence alignments of Picornavirus capsid proteins, in: “Molecular Aspects of Picornavirus Infection and Detection”, B.L. Semler, and E. Ehrefeld, eds., American Society for Microbiology, Washington, D.C.Google Scholar
  134. Parisi, J.M., Costa Giomi, P., Grigera, P., Augé de Mello, P., Bergmann, I.E., La Torre, J.L., and Scodeller, E.A., 1985, Virology 147: 61–71.Google Scholar
  135. Parvin, J.D., Moscona, A., Pan, W.T., Leider, J.M., and Palese, P., 1986, Neasurement of the mutation rates of animal viruses: Influenza A virus and poliovirus type 1, J. Virol., 59: 377–383.PubMedGoogle Scholar
  136. Pelletier, I., Couderc, T., Borzakian, S., Wyckoff, E., Crainic, R., Ehrenfeld, E., and Colbère-Garapin, F., 1991, Characterization of persistent poliovirus mutants selected in human neuroblastoma cells, Virology 180: 729–737.PubMedCrossRefGoogle Scholar
  137. Pevear, D.C., Borkowski, J., Calenoff, M., Oh, C.K., Ostrowski, B., and Lipton, H.L., 1988, Insights into Theiler’s virus neurovirulence based on a genomic comparison of the neurovirulent GDVII and less virulent Be An strains, Virology 165: 1–12.PubMedCrossRefGoogle Scholar
  138. Pilipenko, E.V., Blinov, V.M., Chernov, B.K., Dimitrieva, T.M., and Agol, V.I., 1989a, Conservation of the secondary structure elements of the 5′-untranslated region of cardio-and aphthovirus RNAs, Nucleic Acids Res. 17: 5701–5711.PubMedCrossRefGoogle Scholar
  139. Pilipenko, E.V., Blinov, V.M., Romanova, L.I., Sinyakov, A.N., Maslova, S.V., and Agol, V.I., 1989b, Conserved structural domains in the 5-untranslated region of picornaviral genomes: an analysis of the segment controlling translation and neurovirulence, Virology 168: 201–209.PubMedCrossRefGoogle Scholar
  140. Prabhakar, B.S., Menegus, M.A., and Notkins, A.L., 1985, Detection of conserved and nonconserved epitopes on Coxsackie virus B4: frequency of antigenic change, Virology 146: 302.PubMedCrossRefGoogle Scholar
  141. Provost, P.J., and Hilleman, M.R., 1979, Propagation of human hepatitis A virus in cell culture in vitro, Proc. Soc. Exp. Biol. Med.} 160: 213–221.PubMedGoogle Scholar
  142. Radioff, R.J., and Young, S.A., 1983, Defective interfering particles of encephalomyocarditis virus, J. Gen Virol. 64: 1637–1641.CrossRefGoogle Scholar
  143. Ray, U.R., Aulakh, G.S., Schubert, M., McClintock, P.R., Yoon, J.W., and Notkins, A.L., 1983, Virus-induced diabetes mellitus. XXV. Difference in the RNA fingerprints of diabetogenic and non-diabetogenic variants of encephalomyocarditis virus, J. Gen. Virol. 64: 947–950.PubMedCrossRefGoogle Scholar
  144. Reagan, K.J., Goldberg, B., and Crowell, R.L., 1984, Altered receptor specifity of coxsackievirus B3 after growth in rhabdomyosarcoma cells, J. Virol. 49: 635–640.PubMedGoogle Scholar
  145. Rico-Hesse, R., Pallansch, M.A., Nottay, B.K., and Kew, O.M., 1987, Geographic distribution of wild poliovirus type 1 genotypes, Virology 160: 311–322.PubMedCrossRefGoogle Scholar
  146. Righthand, V.F., and Blackburn, R.V., 1989, Steady-state infection by echovirus 6 associated with nonlytic viral RNA and an unprocessed capsid polypeptide, J. Virol. 63: 5268–5275.PubMedGoogle Scholar
  147. Robertson, B.H., Jansen, R.W., Khanna, B., Totsuka, A., Nainan, O.V., Siegl, G., Widell, A., Margolis, H.S., Isomura, S., Ito, K., Ishizu, T., Moritsugu, Y., and Lemon, S.M., 1992, Genetic relatedness of hepatitis A virus strains recovered from different geographical regions, J. Gen. Virol. 73: 1365–1377.PubMedCrossRefGoogle Scholar
  148. Rodríguez, M., and David, C.S., 1985, Demyelination induced by Theiler’s virus: influence of the H-2 haplotype, J. Immunol. 135: 2145–2148.PubMedGoogle Scholar
  149. Rodríguez, M., Oleszak, E., and Leibowitz, J., 1987, Theiler’s murine encephalomyelitis: a model of demyelination and persistence of virus, Critical Reviews in Immunology 7: 325–365.PubMedGoogle Scholar
  150. Roos, R.P., Richards, O.C., Green, J., and Ehrenfeld, E., 1982, Characterization of a cell culture persistently infected with the DA strain of Theiler’s murine encephalomyelitis virus, J. Virol. 43: 1118–1122.PubMedGoogle Scholar
  151. Rota, J.S., Hummel, K.B., Rota, P.A., and Bellini, W.J., 1992, Genetic variability of the glycoprotein genes of current wild type measles isolates, Virology 188: 135–142.PubMedCrossRefGoogle Scholar
  152. Roux, L., Simon, A.E., and Holland, J.J., 1991, Effects of defective interfering viruses on virus replication and pathogenesis, Advances in Virus Res. 40: 181–211.CrossRefGoogle Scholar
  153. Rueckert, R.R., 1990, Picornaviridae and their replication, in: “Virology”, B.N. Fields, D.M. Knipe et al. eds., Raven Press, New York.Google Scholar
  154. Sedivy, J.M., Capone, J.P., Raj Bhandary, U.L., and Sharp, P.A., 1987, An inducible mammalian amber suppressor: propagation of a poliovirus mutant Cell 50: 379–389.PubMedCrossRefGoogle Scholar
  155. Seibold, H.R., Cottral, G.E., Patty, R.E., and Gailiunas, P., 1964, Apparent modification of foot-and-mouth disease virus after prolonged residence in surviving cells, Amer. J. Vet. Res. 25: 806–814.PubMedGoogle Scholar
  156. Sellers, R.F., 1971, Quantitative aspects of the spread of foot-and-mouth disease, Vet. Bull. 41: 431–439.Google Scholar
  157. Sharief, M.K., Hentges, R., and Ciardi, M., 1991, Intrathecal immune response in patients with the post-polio syndrome, N. Engl. J. Med. 325: 749–755.PubMedCrossRefGoogle Scholar
  158. Sherry, B., Mosser, A.G., Colonno, R.J., and Rueckert, R.R., 1986, Use of monoclonal antibodies to identify four neutralization immunogens on a common cold Picornavirus, human rhinovirus 14, J. Virol. 57: 246–257.PubMedGoogle Scholar
  159. Siegl, G. deChastonay, J., and Kronauer, K., 1984, Propagation and assay of hepatitis A virus in vitro, J. Virol. Methods 9: 53–60.PubMedCrossRefGoogle Scholar
  160. Skern, T., Sommergruber, W., Blaas, D., Pieler, Ch., and Kuechler, E., 1984, Relationship of human rhinovirus strain 2 and poliovirus as indicated by comparison of the polymerase gene regions, Virology 136: 125–132.PubMedCrossRefGoogle Scholar
  161. Sobrino, F., Palma, E.L., Beck, E., Dávila, M., de la Torre, J.C., Negro, P., Villanueva, N., Ortín, J., and Domingo, E., 1986, Fixation of mutations in the viral genome during an outbreak of foot-and-mouth disease: heterogeneity and rate variations, Gene 50: 149–159.PubMedCrossRefGoogle Scholar
  162. Stanway, G., Hughes, P.J., Mountford, R.C., Minor, P.D., and Almond, J.W., 1984, The complete nucleotide sequence of a common cold virus: human rhinovirus 14, Nucleic Acids Res. 12: 7859–7875.PubMedCrossRefGoogle Scholar
  163. Stanway, G., 1990, Structure, function and evolution of picornaviruses, J. Gen. Virol. 71: 2483–2501.PubMedCrossRefGoogle Scholar
  164. Stapleton, J.T., and Lemon, S.M., 1987, Neutralization escape mutants define a dominant immunogenic neutralization site on hepatitis A virus, 1987, J. Virol. 61: 491–498.PubMedGoogle Scholar
  165. Steinhauer, D.A., and Holland, J.J., 1986, Direct method for quantification of extreme polymerase error frequencies at selected single base sites in viral RNA, J. Virol. 57: 219–228.PubMedGoogle Scholar
  166. Takeda, N., Miyamura, K., Ogino, T., Natory, K., Yamazaki, S., Sakwiai, N., Nakazono, N., Ishü, K., and Kono, R., 1984, Evolution of enterovirus type 70: oligonucleotide mapping analysis of RNA genome, Virology 134: 375–388.PubMedCrossRefGoogle Scholar
  167. Takemoto, K.K., and Habel, K., 1959, Virus-cell relationship in a carrier culture of HeLa cell and Coxsackie A9 virus, Virology 7: 28–44.PubMedCrossRefGoogle Scholar
  168. Temin, H., 1989, Is HIV unique or merely different? J. AIDS 2: 1–9.Google Scholar
  169. Theiler, M., 1934, Spontaneous encephalomyelitis of mice — a new virus disease, Science 80: 122–123.PubMedCrossRefGoogle Scholar
  170. Ticehurst, J., Cohen, J.I., Feinstone, S.A., Purcell, R.H., Jansen, R.W., and Lemon, S.M., 1989, Replication of hepatitis A virus: new ideas from studies with cloned cDNA, in: “Molecular Aspects of Picornavirus Infection and Detection”, B.L. Semler, and E. Ehrenfeld, eds., American Society for Microbiology, Washington, D.C.Google Scholar
  171. Tyrrell, D.A.J., 1990, Virus variation and the epidemiology and control of rhinoviruses, in: “Applied Virology Research” vol. 2 “Virus Variability, Epidemiology and Control:, E. Kurstak, R.G. Matrusyk, F.A. Murphy, and M.H.V. Van Regenmortel, eds., Plenum Publishing Co., New York.Google Scholar
  172. Valcarcel, J., and Ortín, J., 1989, Phenotypic hiding: the carry-over of mutations in RNA viruses as shown by detection of mar mutants in influenza virus, J. Virol. 63: 4107–4109.PubMedGoogle Scholar
  173. Vallbracht, A., Hofmann, L., Wurster, K.G., and Flehmig, B., 1984, Persistent infection of human fibroblasts by hepatitis-A virus, J. Gen. Virol. 65: 609–615.PubMedCrossRefGoogle Scholar
  174. van Bekkum, J.G., Frenkel, H.S., Frederiks, H.H.J., and Frenkel, S., 1959, Observations on the carrier state of cattle exposed to foot-and-mouth disease virus, Tijdschr. Diergeneesk. 84: 1159–1164.Google Scholar
  175. Venuti, A., Di Russo, C., del Grosso, N., Patti, A.M., Degener, A.M., Midulla, M., Paña, A., and Pérez-Bercoff, R., 1985, Isolation and molecular cloning of a fast-growing strain of human hepatitis A virus from its double-stranded replicative form, J. Virol. 56: 579–588.PubMedGoogle Scholar
  176. Villaverde, A., Martínez, M.A., Sobrino, F., Dopazo, J., Moya, A., and Domingo, E., 1991, Fixation of mutations at the VP1 gene of foot-and-mouth disease virus: can quasispecies define a transient molecular clock? Gene 103: 147–153.PubMedCrossRefGoogle Scholar
  177. Villaverde, A., Martínez-Salas, E., and Domingo, E., 1988, 3D gene of foot-and-mouth disease virus. Conservation by convergence of average sequences, J. Mol. Biol. 204: 771–776.PubMedCrossRefGoogle Scholar
  178. Vogt, M., and Dulbecco, R., 1958, Properties of a HeLa cell culture with increased resistance to poliomyelitis virus, Virology 5: 425–434.PubMedCrossRefGoogle Scholar
  179. Wain-Hobson, S., 1992, Human immunodeficiency virus type 1 quasispecies in vivo and ex vivo, Curr. Top. Microbiol. Immunol. 176: 181–193.PubMedCrossRefGoogle Scholar
  180. Ward, C.D., and Flanegan, J.B., 1992, Determination of the poliovirus RNA polymerase error frequency at eight sites in the viral genome, J. Virol. 66: 3784–3793.PubMedGoogle Scholar
  181. Weeks-Levy, C., Tatem, J.M., DiMichele, S.J., Waterfield, W., Georgiu, A.F., and Mento, S.J., 1991, Identification and characterization of a new base substitution in the vaccine strain of Sabin 3 poliovirus, Virology 185: 934–937.PubMedCrossRefGoogle Scholar
  182. Weitz, M., and Siegl, G., 1985, Variation among hepatitis A virus strains. I. Genomic variation detected by T1 oligonucleotide mapping, Virus Res. 4: 53.PubMedCrossRefGoogle Scholar
  183. Welsh, C.J.R., Blakemore, W.F., Tonks, P., Borrow, P., and Nash, A.A., 1989, Theiler’s murine encephalomyelitis virus infection in mice: a persistent viral infection of the central nervous system which induces demyelination, in: “Immune Responses, Virus Infections and Disease”, N.J. Dimmock, and P.D. Minor, eds. IRL Press, Oxford.Google Scholar
  184. Westrop, G.D., Wareham, K.A., Evans, D.M.A., Dunn, G., Minor, P.D., Magrath, D.I., Taffs, F., Marsden, S., Skinner, M.A., Schild, G.C., and Almond, J.W., 1989, Genetic basis of attenuation of the Sabin type 3 oral poliovirus vaccine, J. Virol. 63: 1338–1344.PubMedGoogle Scholar
  185. Yang, C-F., De, L., Yang, S-J., Gómez, J.R., Cruz, J.R., Holloway, B.P., Pallansch, M.A., and Kew, O.M., 1992, Genotype-specific in vitro amplification of sequences of the wild type 3 polioviruses from Mexico and Guatemala, Virus Research 24: 277–296.PubMedCrossRefGoogle Scholar
  186. Zimmern, D., 1988, Evolution of RNA viruses, in: “RNA Genetics” vol. 2, E. Domingo, J. Holland, and P. Ahlquist, eds. CRC Press INC., Boca Raton, Florida.Google Scholar
  187. Zurbriggen, A., Thomas, C., Yamada, M., Roos, R.P., and Fujinami, R.S., 1991, Direct evidence of a role for amino acid 101 of VP-1 in central nervous system disease in Theiler’s murine encephalomyelitis virus infection, J.Virol. 65: 1929–1937.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Esteban Domingo
    • 1
  • Cristina Escarmís
    • 1
  • Encarnación Martínez-Salas
    • 1
  • Ana M. Martín Hernández
    • 1
  • Mauricio G. Mateu
    • 1
  • Miguel A. Martínez
    • 1
  1. 1.Centro de Biología Molecular “Severo Ochoa” (CSIC — UAM)Universidad Autónoma de MadridMadridSpain

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