Fidelity Variants and RNA Quasispecies

By now, it is well established that the error rate of the RNA-dependent RNA polymerase (RdRp) that replicates RNA virus genomes is a primary driver of the mutation frequencies observed in RNA virus populations—the basis for the RNA quasispecies. Over the last 10 years, a considerable amount of work has uncovered the molecular determinants of replication fidelity in this enzyme. The isolation of high- and low-fidelity variants for several RNA viruses, in an expanding number of viral families, provides evidence that nature has optimized the fidelity to facilitate genetic diversity and adaptation, while maintaining genetic integrity and infectivity. This chapter will provide an overview of what fidelity variants tell us about RNA virus biology and how they may be used in antiviral approaches.

• Publication year

  2015

• Venue

  Current Topics in Microbiology and Immunology

• Publication date

  2015-10-25

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1007/82_2015_483PMID 26499340PMCID 7121553
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Sequence-Specific Fidelity Alterations Associated with West Nile Virus Attenuation in Mosquitoes

  2015influential reference
• Attenuation of Human Enterovirus 71 High-Replication-Fidelity Variants in AG129 Mice

  2014cited by this paper
• Foot-and-mouth disease virus low-fidelity polymerase mutants are attenuated

  2014cited by this paper
• Variation in RNA Virus Mutation Rates across Host Cells

  2014cited by this paper
• Ribavirin-Resistant Variants of Foot-and-Mouth Disease Virus: the Effect of Restricted Quasispecies Diversity on Viral Virulence

  2014cited by this paper
• The Crystal Structure of a Cardiovirus RNA-Dependent RNA Polymerase Reveals an Unusual Conformation of the Polymerase Active Site

  2014cited by this paper
• Alphavirus Mutator Variants Present Host-Specific Defects and Attenuation in Mammalian and Insect Models

  2014cited by this paper
• Generation and characterization of influenza A viruses with altered polymerase fidelity

  2014influential reference
• Crystal Structure of the Full-Length Japanese Encephalitis Virus NS5 Reveals a Conserved Methyltransferase-Polymerase Interface

  2013cited by this paper
• Crystal Structure of Enterovirus 71 RNA-Dependent RNA Polymerase Complexed with Its Protein Primer VPg: Implication for a trans Mechanism of VPg Uridylylation

  2013cited by this paper
• Vaccine-derived Mutation in Motif D of Poliovirus RNA-dependent RNA Polymerase Lowers Nucleotide Incorporation Fidelity*

  2013influential reference
• An increased replication fidelity mutant of foot-and-mouth disease virus retains fitness in vitro and virulence in vivo.

  2013influential reference
• A study of the virulence in mice of high copying fidelity variants of human enterovirus 71

  2013cited by this paper
• Interrelationship between HIV-1 fitness and mutation rate.

  2013cited by this paper
• A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease

  2012cited by this paper
• Motif D of viral RNA-dependent RNA polymerases determines efficiency and fidelity of nucleotide addition.

  2012influential reference
• Ribavirin-Resistant Mutants of Human Enterovirus 71 Express a High Replication Fidelity Phenotype during Growth in Cell Culture

  2012cited by this paper
• Coxsackievirus B3 mutator strains are attenuated in vivo

  2012cited by this paper
• Isolation of Fidelity Variants of RNA Viruses and Characterization of Virus Mutation Frequency

  2011cited by this paper
• Mutational Robustness of an RNA Virus Influences Sensitivity to Lethal Mutagenesis

  2011cited by this paper
• Arbovirus high fidelity variant loses fitness in mosquitoes and mice

  2011cited by this paper
• A Multi-Step Process of Viral Adaptation to a Mutagenic Nucleoside Analogue by Modulation of Transition Types Leads to Extinction-Escape

  2010cited by this paper
• Long-range interaction networks in the function and fidelity of poliovirus RNA-dependent RNA polymerase studied by nuclear magnetic resonance.

  2010influential reference
• Fidelity Variants of RNA Dependent RNA Polymerases Uncover an Indirect, Mutagenic Activity of Amiloride Compounds

  2010cited by this paper
• Structure of Foot-and-Mouth Disease Virus Mutant Polymerases with Reduced Sensitivity to Ribavirin

  2010cited by this paper
• Structural basis for active site closure by the poliovirus RNA-dependent RNA polymerase

  2010cited by this paper
• Rationalizing the development of live attenuated virus vaccines

  2010cited by this paper
• Infidelity of SARS-CoV Nsp14-Exonuclease Mutant Virus Replication Is Revealed by Complete Genome Sequencing

  2010influential reference
• Dynamics: the missing link between structure and function of the viral RNA-dependent RNA polymerase?

  2009influential reference
• Observations on two types of genetic instability in Escherichia coli.

  2009cited by this paper
• Engineering attenuated virus vaccines by controlling replication fidelity

  2008cited by this paper
• Nucleic acid polymerases employ a general acid for nucleotidyl transfer

  2008cited by this paper
• 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

  2008cited by this paper
• Structure-function relationships among RNA-dependent RNA polymerases.

  2008influential reference
• The Crystal Structure of Coxsackievirus B3 RNA-Dependent RNA Polymerase in Complex with Its Protein Primer VPg Confirms the Existence of a Second VPg Binding Site on Picornaviridae Polymerases

  2008cited by this paper
• Crystal structure of the polymerase PAC–PB1N complex from an avian influenza H5N1 virus

  2008cited by this paper
• Amiloride Derivatives Inhibit Coxsackievirus B3 RNA Replication

  2007cited by this paper
• Crystal Structure of the RNA Polymerase Domain of the West Nile Virus Non-structural Protein 5*

  2007cited by this paper
• The structure of a birnavirus polymerase reveals a distinct active site topology

  2007cited by this paper
• Sequential structures provide insights into the fidelity of RNA replication

  2007influential reference
• The cost of replication fidelity in human immunodeficiency virus type 1

  2007cited by this paper
• High Fidelity of Murine Hepatitis Virus Replication Is Decreased in nsp14 Exoribonuclease Mutants

  2007influential reference
• Structure-Function Relationships of the Viral RNA-dependent RNA Polymerase

  2007cited by this paper
• Crystal Structure of Poliovirus 3CD Protein: Virally Encoded Protease and Precursor to the RNA-Dependent RNA Polymerase

  2007cited by this paper
• Crystal Structure of the Dengue Virus RNA-Dependent RNA Polymerase Catalytic Domain at 1.85-Angstrom Resolution

  2007cited by this paper
• Two proton transfers in the transition state for nucleotidyl transfer catalyzed by RNA- and DNA-dependent RNA and DNA polymerases

  2007cited by this paper
• A comparison of viral RNA-dependent RNA polymerases.

  2006cited by this paper
• Foot-and-Mouth Disease Virus Mutant with Decreased Sensitivity to Ribavirin: Implications for Error Catastrophe

  2006cited by this paper
• Structural and Functional Characterization of Sapovirus RNA-Dependent RNA Polymerase

  2006cited by this paper
• Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population

  2006cited by this paper
• Quasispecies dynamics and RNA virus extinction.

  2005cited by this paper
• Remote Site Control of an Active Site Fidelity Checkpoint in a Viral RNA-dependent RNA Polymerase*

  2005cited by this paper
• The cost of replication fidelity in an RNA virus.

  2005cited by this paper
• Increased Fidelity Reduces Poliovirus Fitness and Virulence under Selective Pressure in Mice

  2005cited by this paper
• Crystal Structure of Complete Rhinovirus RNA Polymerase Suggests Front Loading of Protein Primer

  2005cited by this paper
• Poliovirus RNA-dependent RNA polymerase (3Dpol): kinetic, thermodynamic, and structural analysis of ribonucleotide selection.

  2004influential reference
• Structural basis for proteolysis‐dependent activation of the poliovirus RNA‐dependent RNA polymerase

  2004cited by this paper
• Structure of Foot-and-Mouth Disease Virus RNA-dependent RNA Polymerase and Its Complex with a Template-Primer RNA*

  2004cited by this paper
• The structure of the RNA-dependent RNA polymerase from bovine viral diarrhea virus establishes the role of GTP in de novo initiation.

  2004cited by this paper
• Poliovirus RNA-dependent RNA polymerase (3Dpol): pre-steady-state kinetic analysis of ribonucleotide incorporation in the presence of Mn2+.

  2004cited by this paper
• Poliovirus RNA-dependent RNA polymerase (3Dpol): pre-steady-state kinetic analysis of ribonucleotide incorporation in the presence of Mg2+.

  2004cited by this paper
• Crystal Structure of Norwalk Virus Polymerase Reveals the Carboxyl Terminus in the Active Site Cleft*

  2004cited by this paper
• The structural basis for RNA specificity and Ca2+ inhibition of an RNA-dependent RNA polymerase.

  2004cited by this paper
• The crystal structure of the RNA-dependent RNA polymerase from human rhinovirus: a dual function target for common cold antiviral therapy.

  2004cited by this paper
• A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity

  2003cited by this paper
• Substrate complexes of hepatitis C virus RNA polymerase (HC-J4): structural evidence for nucleotide import and de-novo initiation.

  2003cited by this paper
• Crystal Structures of Active and Inactive Conformations of a Caliciviral RNA-dependent RNA Polymerase*

  2002cited by this paper
• RNA Synthesis in a Cage — Structural Studies of Reovirus Polymerase 3 redoxin molecule

  2002cited by this paper
• Foot-and-mouth disease virus.

  2002cited by this paper
• RNA synthesis in a cage--structural studies of reovirus polymerase lambda3.

  2002cited by this paper
• A mechanism for initiating RNA-dependent RNA polymerization

  2001cited by this paper
• Poliovirus RNA-dependent RNA Polymerase (3Dpol)

  2000cited by this paper
• Poliovirus RNA-dependent RNA polymerase (3D(pol)). Assembly of stable, elongation-competent complexes by using a symmetrical primer-template substrate (sym/sub).

  2000cited by this paper
• 3′-Azido-3′-Deoxythymidine (AZT) and AZT-Resistant Reverse Transcriptase Can Increase the In Vivo Mutation Rate of Human Immunodeficiency Virus Type 1

  2000cited by this paper
• Mutation rates among RNA viruses.

  1999influential reference
• Crystal structure of the RNA-dependent RNA polymerase from hepatitis C virus reveals a fully encircled active site

  1999cited by this paper
• Increased polymerase fidelity of lamivudine-resistant HIV-1 variants does not limit their evolutionary potential.

  1999cited by this paper
• Poliovirus RNA-dependent RNA polymerase (3D(pol)). Divalent cation modulation of primer, template, and nucleotide selection.

  1999cited by this paper
• Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus.

  1999cited by this paper
• Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus.

  1999cited by this paper
• Structural biology: A mechanism for all polymerases

  1998cited by this paper
• Rates of spontaneous mutation.

  1998influential reference
• Structure of the RNA-dependent RNA polymerase of poliovirus.

  1997cited by this paper
• Role of mutator alleles in adaptive evolution

  1997cited by this paper
• Evolution of high mutation rates in experimental populations of E. coli

  1997cited by this paper
• Mutational studies of human immunodeficiency virus type 1 reverse transcriptase : the involvement of residues 183 and 184 in the fidelity of DNA synthesis

  1996cited by this paper
• High Mutation Frequencies Among Escherichia coli and Salmonella Pathogens

  1996cited by this paper
• Enhanced Fidelity of 3TC-Selected Mutant HIV-1 Reverse Transcriptase

  1996cited by this paper
• Human immunodeficiency virus type 1 reverse transcriptase: role of Tyr115 in deoxynucleotide binding and misinsertion fidelity of DNA synthesis.

  1996cited by this paper
• Base selection, proofreading, and mismatch repair during DNA replication in Escherichia coli.

  1993cited by this paper
• Heterogeneity of the mutation rates of influenza A viruses: isolation of mutator mutants

  1992cited by this paper
• DNA polymerization in the absence of exonucleolytic proofreading: in vivo and in vitro studies.

  1991cited by this paper
• The phylogeny of RNA-dependent RNA polymerases of positive-strand RNA viruses.

  1991influential reference
• Generation of genetic diversity in herpes simplex virus: an antimutator phenotype maps to the DNA polymerase locus.

  1984cited by this paper
• Reversion to neurovirulence of the live-attenuated Sabin type 3 oral poliovirus vaccine.

  1984cited by this paper
• Incidence of mutator strains in Escherichia coli and coliforms in nature.

  1981cited by this paper
• Control of mutation frequency by bacteriophage T4 DNA polymerase. I. The CB120 antimutator DNA polymerase is defective in strand displacement.

  1976cited by this paper
• Mutator activity of petite strains of Saccharomyces cerevisiae.

  1976cited by this paper
• Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity.

  1974cited by this paper
• Studies on the biochemical basis of spontaneous mutation. I. A comparison of the deoxyribonucleic acid polymerases of mutator, antimutator, and wild type strains of bacteriophage T4.

  1972cited by this paper

• Egress-enhancing mutation reveals inefficiency of non-enveloped virus cell exit

  2025cites this paper
• Programmable self-replicating JEV nanotherapeutics redefine RNA delivery in ALS

  2025influential citation
• Egress-enhancing mutation reveals the inefficiency of non-enveloped virus cell exit

  2025cites this paper
• Differential Virulence and Host-Specific Fitness of Regionally Distinct Human-Derived Powassan Virus Lineage 2 Strains

  2025cites this paper
• Polyoxometalate exerts broad-spectrum activity against human respiratory viruses hampering viral entry.

  2024cites this paper
• B cells expressing mutated IGHV1-69–encoded antigen receptors related to virus neutralization show lymphoma-like transcriptomes in patients with chronic HCV infection

  2024cites this paper
• Fidelity Characterization of Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus and NADC30-like Strain

  2024cites this paper
• The Intra-Host Evolution of SARS-CoV-2 After Neutralizing Antibody Therapy, Revealed by Nanopore Sequencing

  2024cites this paper
• Neutralization of African enterovirus A71 genogroups by antibodies to canonical genogroups.

  2023cites this paper
• Mutational analysis of catalytic site domain of CCHFV L RNA segment

  2023cites this paper
• Scientific Session of the General Meeting of the RAS Members “The Role of Science in Overcoming Pandemics and Postcrisis Development of Society” Mechanisms of Coronavirus Genome Stability As Potential Targets for Antiviral Drugs

  2022cites this paper
• A Virus Is a Community: Diversity within Negative-Sense RNA Virus Populations

  2022cites this paper
• Genomic diversity contributes to the neuroinvasiveness of the Yellow fever French neurotropic vaccine

  2021cites this paper
• Current view on novel vaccine technologies to combat human infectious diseases

  2021cites this paper
• Allosteric and dynamic control of RNA-dependent RNA polymerase function and fidelity.

  2021cites this paper
• Mutation Rates, Mutation Frequencies, and Proofreading-Repair Activities in RNA Virus Genetics

  2021cites this paper
• Rescuing eGFP-Tagged Canine Distemper Virus for 40 Serial Passages Separately in Ribavirin- and Non-Treated Cells: Comparative Analysis of Viral Mutation Profiles

  2021cites this paper
• Mutation Profiles of eGFP-Tagged Small Ruminant Morbillivirus During 45 Serial Passages in Ribavirin-Treated Cells

  2021cites this paper
• Genome Evolution of Two Genetically Homogeneous Infectious Bursal Disease Virus Strains During Passages in vitro and ex vivo in the Presence of a Mutagenic Nucleoside Analog

  2021cites this paper
• Tradeoffs for a viral mutant with enhanced replication speed

  2021cites this paper
• Darwinian principles acting on highly mutable viruses

  2020cites this paper
• SARS-CoV-2 Quasispecies Mediate Rapid Virus Evolution and Adaptation

  2020cites this paper
• A 5-Year Review of Senecavirus A in China since Its Emergence in 2015

  2020cites this paper
• Increased RNA virus population diversity improves adaptability

  2020cites this paper
• Rescue of Senecavirus A to uncover mutation profiles of its progenies during 80 serial passages in vitro.

  2020cites this paper
• Rapid SARS-CoV-2 Adaptation to Available Cellular Proteases

  2020cites this paper
• Molecular basis of genetic variation of viruses

  2019cites this paper
• Trends in antiviral strategies

  2019cites this paper
• Stronger together: Multi-genome transmission of measles virus.

  2019cites this paper
• Expanding Repertoire of Plant Positive-Strand RNA Virus Proteases

  2019cites this paper
• Directed evolution as a tool for the selection of oncolytic RNA viruses with desired phenotypes

  2019cites this paper
• Tyr82 Amino Acid Mutation in PB1 Polymerase Induces an Influenza Virus Mutator Phenotype

  2019cites this paper
• A proofreading-impaired herpesvirus generates populations with quasispecies-like structure

  2019cites this paper
• Viral quasispecies

  2019cites this paper
• Viral fitness: history and relevance for viral pathogenesis and antiviral interventions.

  2019cites this paper
• Characterization of Mutational Tolerance of a Viral RNA–Protein Interaction

  2019cites this paper
• Broad and Dynamic Diversification of Infectious Hepatitis C Virus in a Cell Culture Environment

  2019cites this paper
• Contribution of a Multifunctional Polymerase Region of Foot-and-Mouth Disease Virus to Lethal Mutagenesis

  2018cites this paper
• Rare haplotype load as marker for lethal mutagenesis

  2018cites this paper
• Emergency Services of Viral RNAs: Repair and Remodeling

  2018cites this paper
• Title Analysis of IAV Replication and Co-infection Dynamics bya Versatile RNA Viral Genome Labeling Method

  2018cites this paper
• Structural and Nonstructural Genes Contribute to the Genetic Diversity of RNA Viruses

  2018cites this paper
• A speed–fidelity trade-off determines the mutation rate and virulence of an RNA virus

  2018cites this paper
• Quasispecies and virus

  2018cites this paper
• Quasispecies and virus

  2018cites this paper
• Foot-and-mouth disease virus type O specific mutations determine RNA-dependent RNA polymerase fidelity and virus attenuation.

  2018cites this paper
• Extinction of West Nile Virus by Favipiravir through Lethal Mutagenesis

  2017cites this paper
• Dimension Reduction and Signal Decomposition for Genotype-Phenotype Relations

  2017cites this paper
• Molecular and Functional Bases of Selection against a Mutation Bias in an RNA Virus

  2017influential citation
• Analysis of IAV Replication and Co-infection Dynamics by a Versatile RNA Viral Genome Labeling Method.

  2017cites this paper
• Attenuation of Foot-and-Mouth Disease Virus by Engineered Viral Polymerase Fidelity

  2017cites this paper
• Deep sequencing in the management of hepatitis virus infections.

  2017cites this paper
• Virus population dynamics during infection.

  2017cites this paper
• Pressure for Pattern-Specific Intertypic Recombination between Sabin Polioviruses: Evolutionary Implications

  2017cites this paper
• Rôle de la protéine PB1 dans la fidélité du complexe polymérase des virus influenza

  2017influential citation
• Population genetic analysis of a parasitic mycovirus to infer the invasion history of its fungal host

  2017cites this paper
• Serotype-specific interactions among functional domains of dengue virus 2 nonstructural proteins (NS) 5 and NS3 are crucial for viral RNA replication

  2017cites this paper
• Attenuation of RNA viruses by redirecting their evolution in sequence space

  2017cites this paper
• 1st Workshop of the Canadian Society for Virology

  2017cites this paper
• Involvement of a joker mutation in a polymerase-independent lethal mutagenesis escape mechanism

  2016cites this paper
• Norovirus Polymerase Fidelity Contributes to Viral Transmission In Vivo

  2016cites this paper
• Viral quasispecies complexity measures.

  2016cites this paper
• Mechanisms of viral mutation

  2016cites this paper
• Resistance of Hepatitis C Virus to Inhibitors: Complexity and Clinical Implications

  2015cites this paper
• Molecular Basis of Genetic Variation of Viruses

  2015cites this paper
• Trends in Antiviral Strategies

  2015cites this paper