Detection and Biological Implications of Genetic Memory in Viral Quasispecies

  • Esteban Domingo
  • Carmen M. Ruiz-Jarabol
  • Armando Ariasl
  • Cristina Escarmís
  • Carmen Molina-París
  • Carlos Briones
  • Eric Baranowski
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 248)


Infection of an organism or cells in culture with a single infectious genome of an RNA virus results in the prompt formation of a spectrum of mutants, as has been experimentally documented with representatives of the major groups of RNA virus pathogens.1 This fact is critical for the understanding of viral pathogenesis, since it means that a virus does not exist as a genetically defined entity but rather as a distribution of genomes which differ from each other in one or several positions in their nucleotide sequence (figure 1). Some of these closely related but non-identical genomes may have biological properties which differ from those of the average viral population or from those of other components of the mutant spectrum. Thus, genetic heterogeneity is paralleled by a phenotypic heterogeneity in viral populations. Well documented examples are the presence in mutant spectra of variants with altered antigenicity, host cell tropism, capacity to induce interferon, decreased sensitivity to antiviral inhibitors, or variants which display altered patterns of viral gene expression (specific examples and reviews in refs. 2-13).


Mutant Spectrum Fitness Gain Viral Quasispecies Memory Level Memory Genome 
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.


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  1. 1.
    Domingo E, Webster RG, Holland, JJ, eds. Origin and Evolution of Viruses. San Diego, California: Academic Press, 1999.Google Scholar
  2. 2.
    Marcus PI, Rodriguez LL, Sekellick, M. Interferon Induction as a Quasispecies Marker of Vesicular Stomatitis Virus Populations. J J Virol 1998;72:542–549.Google Scholar
  3. 3.
    Domingo E. Biological Significance of Viral Quasispecies. Viral Hepatitis Reviews 1996;2:247–261.Google Scholar
  4. 4.
    Flint SJ, Enquist LW, Krug RM, et al. Principles of Virology. Molecular Biology, Pathogenesis and Control. Washington DC: ASM Press, 2000.Google Scholar
  5. 5.
    McMichael AJ, Phillips RE. Escape of Human Immunodeficiency Virus from Immune Control. Annu Rev Immunol 1997;15:271–296.PubMedCrossRefGoogle Scholar
  6. 6.
    Casadevall A. Crisis in Infectious Diseases: Time for a New Paradigm? Clin Infect Dis 1996;23:790–794.PubMedCrossRefGoogle Scholar
  7. 7.
    Weidt G, Deppert W, Utermohlen O, et al. Emergence of Virus Escape Mutants after Immunization with Epitope Vaccine. J Virol 1995:69;7147–7151.PubMedGoogle Scholar
  8. 8.
    Weiner A, Erickson AL, Kansopon J, et al. Persistent Hepatitis C Virus Infection in a Chimpanzee is Associated with Emergence of a Cytotoxic T Lymphocyte Escape Variant. Proc Natl Acad Sci USA 1995;92:2755–2759.PubMedCrossRefGoogle Scholar
  9. 9.
    Taboga O, Tami C, Carrillo E, et al. A Large-Scale Evaluation of Peptide Vaccines Against Foot-and-Mouth Disease: Lack of Solid Protection in Cattle and Isolation of Escape Mutants. J Virol 1997;71:2606–2614.PubMedGoogle Scholar
  10. 10.
    Domingo E, Holland JJ. RNA Virus Mutations and Fitness for Survival. Annu Rev Microbiol 1997;51:151–178.PubMedCrossRefGoogle Scholar
  11. 11.
    Domingo E, Mas A, Yuste E, et al. Virus Population Dynamics, Fitness Variations and the Control of Viral Disease: An Update. Progress in Drug Res 2001;57:77–115.Google Scholar
  12. 12.
    Baranowski E, Ruiz-Jarabo CM, Domingo E. Evolution of Cell Recognition by Viruses. Science 2001:292:1102–1105.PubMedCrossRefGoogle Scholar
  13. 13.
    Sevilla N, Domingo E, de la Torre JC. Contribution of LCMV Towards Deciphering Biology of Quasispecies In Vivo. Curr Top Microbiol Immunol 2002;263:197–220.PubMedCrossRefGoogle Scholar
  14. 14.
    Steinhauer DA, Domingo E, Holland JJ. Lack of Evidence for Proofreading Mechanisms Associated with an RNA Virus Polymerase. Gene 1992; 122:281–288.PubMedCrossRefGoogle Scholar
  15. 15.
    Sousa R. Structural and Mechanistic Relationships Between Nucleic Acid Polymerases. Trends Biochem Sci 1996;21:186–190.PubMedGoogle Scholar
  16. 16.
    Hansen J, Long AM, Schultz S. Structure of the RNA-Dependent RNA Polymerase of Poliovirus. Structure 1997;15:1109–1122.CrossRefGoogle Scholar
  17. 17.
    Batschelet E, Domingo E, Weissmann C. The Proportion of Revenant and Mutant Phage in a Growing Population, as a Function of Mutation and Growth Rate. Gene 1976;1:27–32.PubMedCrossRefGoogle Scholar
  18. 18.
    Drake JW, Holland JJ. Mutation Rates Among RNA Viruses. Proc Natl Acad Sci USA 1999;96:13910–13913.PubMedCrossRefGoogle Scholar
  19. 19.
    Domingo E, Sabo D, Taniguchi T, et al. Nucleotide Sequence Heterogeneity of an RNA Phage Population. Cell 1978:13;735–744.PubMedCrossRefGoogle Scholar
  20. 20.
    Domingo E, Biebricher C, Eigen M, et al. eds. Quasispecies and RNA Virus Evolution: Principles and Consequences. Austin, Texas: Landes Bioscience, 2001.Google Scholar
  21. 21.
    Eigen M, Schuster, P. The Hypercycle. A Principle of Natural Self-Organization. Berlin: Springer, 1979.Google Scholar
  22. 22.
    Eigen M, Biebricher CK. “Sequence Space and Quasispecies Distribution.” In RNA Genetics, Domingo E, Ahlquist P, Holland JJ, eds. Vol. 3, pp. 211–245, Boca Raton, FL: CRC Press, 1988.Google Scholar
  23. 23.
    Eigen M. Natural Selection: A Phase Transition? Biophys Chem 2000;85:101–123.PubMedCrossRefGoogle Scholar
  24. 24.
    Crandall KA, ed. The Evolution of HIV, Baltimore and London: The Johns Hopkins University Press, 1999.Google Scholar
  25. 25.
    Pawlotsky JM. Hepatitis C Virus Resistance to Antiviral Therapy. Hepatology 2000;32:889–896.PubMedCrossRefGoogle Scholar
  26. 26.
    Pawlotsky JM, Germanidis G, Neumann AU, et al. Interferon Resistance of Hepatitis C Virus Genotype 1b: Relationship to Nonstructural 5A Gene Quasispecies Mutations. Virol. 1998;72:2795–2805.Google Scholar
  27. 27.
    Forns X, Purcell RH, Bukh J. Quasispecies in Viral Persistence and Pathogenesis of Hepatitis C Virus. Trends Microbiol 1999;7:402–410.PubMedCrossRefGoogle Scholar
  28. 28.
    Farci P, Strazzera R, Alter HJ, et al. Early Changes in Hepatitis C Viral Quasispecies During Interferon Therapy Predict the Therapeutic Outcome. Proc Natl Acad Sci USA 2002;99:3081–3086.PubMedCrossRefGoogle Scholar
  29. 29.
    Domingo E, Holland JJ. Complications of RNA Heterogeneity for the Engineering of Virus Vaccines and Antiviral Agents. Genet Eng 1992;14:13–31.CrossRefGoogle Scholar
  30. 30.
    Holland JJ, de La Torre JC, Steinhauer DA. RNA Virus Populations as Quasispecies. Curr Top Microbiol Immunol 1992;176:1–20.PubMedCrossRefGoogle Scholar
  31. 31.
    de la Torre JC, Holland JJ. RNA Virus Quasispecies Populations Can Suppress Vastly Superior Mutant Progeny. J Virol 1990;64:6278–6281.PubMedGoogle Scholar
  32. 32.
    Gerrish PJ, Lenski RE. The Fate of Competing Beneficial Mutations in an Asexual Population. Genetica 1998;103:127–144.CrossRefGoogle Scholar
  33. 33.
    Miralles R, Gerrish PJ, Moya A, et al. Clonal Interference and the Evolution of RNA Viruses. Science 1999;285:1745–1747.PubMedCrossRefGoogle Scholar
  34. 34.
    Teng MN, Oldstone MB, de la Torre JC. Suppression of Lymphocytic Choriomeningitis Virus-Induced Growth Hormone Deficiency Syndrome by Disease-Negative Virus Variants. Virology 1996;223:113–119.PubMedCrossRefGoogle Scholar
  35. 35.
    Chumakov KM, Powers LB, Noonan KE, et al. Correlation Between Amount of Virus with Altered Nucleotide Sequence and the Monkey Test for Acceptability of Oral Poliovirus Vaccine S Proc Natl Acad Sci USA 1991;88:199–203.CrossRefGoogle Scholar
  36. 36.
    Lohmann V, Körner F, Dobierzewska A, et al. Mutations in Hepatitis C Virus RNAs Conferring Cell Culture Adaptation. J Virol 2001;75:1437–1449.PubMedCrossRefGoogle Scholar
  37. 37.
    Guo JT, Bichko VV, Seeger CJ. Effect of Alpha Interferon on the Hepatitis C Virus Replicon. J Virol 2001;75:8516–8523.PubMedCrossRefGoogle Scholar
  38. 38.
    Baranowski E, Ruíz-Jarabo CM, Lim P, et al. Foot-and-Mouth Disease Virus Lacking the VP1 G-H Loop: the Mutant Spectrum Uncovers Interactions Among Antigenic Sites for Fitness Gain. Virology 2001;288:192–202.PubMedCrossRefGoogle Scholar
  39. 39.
    Cabot B, Martell M, Esteban Jl, et al. Longitudinal Evaluation of the Structure of Replicating and Circulating Hepatitis C Virus Quasispecies in Nonprogressive Chronic Hepatitis C Patients. J Virol 2001;75:12005–12013.PubMedCrossRefGoogle Scholar
  40. 40.
    Arias A, Lázaro E, Escarmís C, et al. Molecular Intermediates of Fitness Gain of an RNA Virus: Characterization of a Mutant Spectrum by Biological and Molecular Sloning. J Gen Virol 2001;82:1049–1060.PubMedGoogle Scholar
  41. 41.
    Núñez Jl, Baranowski E, Molina N, et al. A Single Amino Acid Substitution in Nonstructural Protein 3A can Mediate Adaptation of Foot-and-Mouth Disease Virus to the Guinea Pig. J Virol 2001;75:3977–3983.PubMedCrossRefGoogle Scholar
  42. 42.
    Domingo E. Viruses at the Edge of Adaptation. Virology 2000;270:251–253.PubMedCrossRefGoogle Scholar
  43. 43.
    Ruíz-Jarabo CM, Arias A, Baranowski E, et al. Memory in Viral Quasispecies. J Virol 2000;74:3543–3547.PubMedCrossRefGoogle Scholar
  44. 44.
    Ruíz-Jarabo CM, Arias A, Molina-Paris C, et al. Duration and Fitness Dependence of Quasispecies Memory. J Mol Biol 2002;315:285–296.PubMedCrossRefGoogle Scholar
  45. 45.
    Domingo E, Ruiz-Jarabo CM, Sierra S, et al. Emergence and Selection of RNA Virus Variants: Memory and Extinction. Virus Res 2002;82:39–44.PubMedCrossRefGoogle Scholar
  46. 46.
    Acharya R, Fry E, Stuart D, et al. The Three-Dimensional Structure of Foot-and- Mouth Disease Virus at 2.9 Â Resolution. Nature 1989;337:709–716.PubMedCrossRefGoogle Scholar
  47. 47.
    Mateu MG. Antibody Recognition of Picornaviruses and Escape from Neutralization: A Structural View. Virus Res 1995;38:1–24.PubMedCrossRefGoogle Scholar
  48. 48.
    Martinez MA, Verdaguer N, Mateu MG, et al. Evolution Subverting Essentiality: Dispensability of the Cell Attachment Arg-Gly-Asp Motif in Multiply Passaged Foot-and-Mouth Disease Virus. Proc Natl Acad Sci USA 1997;94:6798–6802.PubMedCrossRefGoogle Scholar
  49. 49.
    Ruíz-Jarabo CM, Sevilla N, Dávila M, et al. Antigenic Properties and Population Stability of a Foot-and-Mouth Disease Virus with an Altered Arg-Gly-Asp Receptor-Recognition Motif. J Gen Virol 1999;80:1899–1909.PubMedGoogle Scholar
  50. 50.
    Baranowski E, Ruíz-Jarabo CM, Sevilla N, et al. Cell Recognition by Foot-and- Mouth Disease Virus that Lacks the RGD Integrin-Binding Motif: Flexibility in Aphthovirus Receptor Usage. J Virol 2000;74:1641–1647.PubMedCrossRefGoogle Scholar
  51. 51.
    Escarmís C, Dávila M, Domingo EJ. Multiple Molecular Pathways for Fitness Recovery of an RNA Virus Debilitated by Operation of Muller’s Ratchet. J Mol Biol 1999;285:495–505.PubMedCrossRefGoogle Scholar
  52. 52.
    Novella IS, Duarte EA, Elena SF, et al. Exponential Increases of RNA Virus Fitness During Large Population Transmissions. J Proc Natl Acad Sci USA 1995;92:5841–5844.CrossRefGoogle Scholar
  53. 53.
    Chao L. Fitness of RNA Virus Decreased by Muller’s Ratchet. Nature 1990;348:454–455.PubMedCrossRefGoogle Scholar
  54. 54.
    Duarte E, Clarke D, Moya A, et al. Rapid Fitness Losses in Mammalian RNA Virus Clones Due to Muller’s Ratchet. Proc Natl Acad Sci USA 1992;89:6015–6019.PubMedCrossRefGoogle Scholar
  55. 55.
    Escarmís C, Dávila M, Charpentier N, et al. Genetic Lesions Associated with Muller’s Ratchet in an RNA Virus. J Mol Biol 1996;264:255–267.PubMedCrossRefGoogle Scholar
  56. 56.
    Escarmís C, Gomez-Mariano G, Dávila M, et al. Resistance to Extinction of Low Fitness Virus Subjected to Plaque-to-Plaque Transfers: Diversification by Mutation Clustering. J Mol Biol 2002;315: 647–661.PubMedCrossRefGoogle Scholar
  57. 57.
    Hertogs K, de Bethune MP, Miller V, et al. A Rapid Method for Simultaneous Detection of Phenotypic Resistance to Inhibitors of Protease and Reverse Transcriptase in Recombinant Human Immunodeficiency Virus Type 1 Isolates from Patients Treated with Antiretroviral Drugs. Antimicrob Agents Chemother 1998;42:269–276.PubMedCrossRefGoogle Scholar
  58. 58.
    Hirsch M S, Brun-Vezinet F, D’Aquila RT, et al. Anti retroviral Drug Resistance Testing in Adult HIV-1 Infection: Recommendations of an International AIDS Society-USA Panel. JAMA 2000;283:2417–2426.PubMedCrossRefGoogle Scholar
  59. 59.
    Schuurman R, Demeter L, Reichelderfer P, et al. Worldwide Evaluation of DNA Sequencing Approaches for Identification of Drug Resistance Mutations in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase. J Clin Microbiol 1999;37:2291–2296.PubMedGoogle Scholar
  60. 60.
    Frate AJ, Chaput CC, Weber JN, et al. HIV-1 Resistance Genotyping by Sequencing Produces Inconsistent Results for Mixed Viral Populations. AIDS 2000;14,1473–1475.CrossRefGoogle Scholar
  61. 61.
    Wilson JW, Bean P, Robins T, et al. Comparative Rvaluation of Three Human Immunodeficiency Virus Genotyping Systems: The HIV-GenotypR Method, the HIV PRT Gene Chip Assay, and the HIV-1 RT Line Probe Assay. J Clin Microbiol 2000;38,3022–3028.PubMedGoogle Scholar
  62. 62.
    Schena M, ed. Microarray Biochip Technology. Sunnyvale, CA: Eaton Publishing, 2000.Google Scholar
  63. 63.
    Hacia JG, Makalowski W, Edgemon K, et al. Evolutionary Sequence Comparisons Using High-Density Oligonucleotide Arrays. Nat Genet 1998; 18, 155–158.PubMedCrossRefGoogle Scholar
  64. 64.
    Gerry NP, Witowski NE, Day J, et al. Universal DNA Microarray Method for Multiplex Detection of Low Abundance Point Mutations. J Mol Biol 1999;292,251–262.CrossRefGoogle Scholar
  65. 65.
    Buetow KH, Edmonson M, MacDonald R, et al. High-Throughput Development and Characterization of a Genomewide Collection of Gene-Based Single Nucleotide Polymorphism Markers by Chip-Based Matrix-Assisted Laser Desorption/lonization Time-of-Flight Mass Spectrometry. Proc Natl Acad Sci USA 2001;98:581–584.PubMedCrossRefGoogle Scholar
  66. 66.
    Kozal MJ, Shah N, Shen N, et al. Extensive Polymorphisms Observed in HIV-1 Clade B Protease Gene Using High-Density Oligonucleotide Arrays. Nat Med 1996:2:753–759.PubMedCrossRefGoogle Scholar
  67. 67.
    Amexis G, Oeth P, Abel K, Ivshina A, et al. Quantitative Mutant Analysis of Viral Quasispecies by Chip-Based Matrix-Assisted Laser Desorption/lonization Time of-Flight Mass Spectrometry. Proc Natl Acad Sci USA 2001; 98:12097–12102.PubMedCrossRefGoogle Scholar
  68. 68.
    Martell M, Esteban Jl, Quer J, et al. Hepatitis C Virus (HCV) Circulates as a Population of Different but Closely Related Genomes: Quasispecies Nature of HCV Genome Distribution. J Virol 1992;66:3225–3229.PubMedGoogle Scholar
  69. 69.
    Borrow P, Lewicki H, Wei X, et al. Antiviral Pressure Exerted by HIV-1-Specific Cytotoxic T Lymphocytes (CTLs) During Primary Infection Demonstrated by Rapid Selection of CTL Escape Virus. Nat Med 1997; 3:205–211.PubMedCrossRefGoogle Scholar
  70. 70.
    Briones C, Mas A, Gomez-Mariano G, et al. Dynamics of Dominance of a Dipeptide Insertion in Reverse Transcriptase of HIV-1 from Patients Subjected to Prolongued Therapy. Virus Res 2000;66:13–26.PubMedCrossRefGoogle Scholar
  71. 71.
    Karlsson AC, Gaines H, Sallberg M, et al. Reappearance of Founder Virus Sequence in Human Immunodeficiency Virus Type 1-Infected Patients. J Virol 1999;73:6191–6196.PubMedGoogle Scholar
  72. 72.
    Wyatt CA, Andrus L, Brotman B, et al. Immunity in Chimpanzees Chronically Infected with Hepatitis C Virus: Role of Minor Quasispecies in Reinfection. J Virol 1998;72:1725–1730.PubMedGoogle Scholar
  73. 73.
    Lau DT, Khokhar MF, Doo E, et al. Long-Term Therapy of Chronic Hepatitis B with Lamivudine. Hepatology 2000;32:828–834.PubMedCrossRefGoogle Scholar
  74. 74.
    Borman AM, Paulous S, Clavel FJ. Resistance of Human Immunodeficiency Virus Type 1 to Protease Inhibitors: Selection of Resistance Mutations in the Presence and Absence of the Drug. Gen Virol 1996;77:419–426.CrossRefGoogle Scholar
  75. 75.
    Nijhuis M, Schuurman R, de Jong D, et al. Increased Fitness of Drug Resistant HIV-1 Protease as a Result of Acquisition of Compensatory Mutations during Suboptimal Therapy. AIDS 1999;13:2349–2359.PubMedCrossRefGoogle Scholar
  76. 76.
    Goudsmit J, de Ronde A, de Rooij E, et al. Broad Spectrum of In Vivo Fitness of Human Immunodeficiency Virus Type 1 Subpopulations Differing at Reverse Transcriptase Codons 41 and 215. J Virol 1997;71:4479–4484.PubMedGoogle Scholar
  77. 77.
    Yerly S, Rakik A, De Loes SK, et al. Switch to Unusual Amino Acids at Codon 215 of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene in Seroconvertors Infected with Zidovudine-Resistant Variants. J Virol 1998;72:3520–3523.PubMedGoogle Scholar
  78. 78.
    de Ronde A, van Dooren M, van Der Hoek L, et al. Establishment of New Transmissible and Drug-Sensitive Human Immunodeficiency Virus Type 1 Wild Types Due to Transmission of Nucleoside Analogue-Resistant Virus. J Virol 2001;75:595–602.PubMedCrossRefGoogle Scholar
  79. 79.
    Garcia-Lerma JG, Nidtha S, Blumoff K, et al. Increased Ability for Selection of Zidovudine Resistance in a Distinct Class of Wild-Type HIV-1 from Drug-Naïve Persons. Proc Natl Acad Sci USA 2001;98:13907–13912.PubMedCrossRefGoogle Scholar
  80. 80.
    Rose S. The Making of Memory. From Molecules to Mind. Toronto, London: Bantam Books, 1995.Google Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Esteban Domingo
    • 1
    • 2
  • Carmen M. Ruiz-Jarabol
    • 1
  • Armando Ariasl
    • 1
  • Cristina Escarmís
    • 1
  • Carmen Molina-París
    • 2
  • Carlos Briones
    • 2
  • Eric Baranowski
    • 1
    • 3
  1. 1.Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM)Universidad Autónoma de Madrid, CantoblancoMadridSpain
  2. 2.Mathematics InstituteUniversity of WarwickCoventryUK
  3. 3.CISA-lNIA, ValdeolmosMadridSpain

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