Determinants of RNA virus evolution

Summary

Principal Investigator: I S Novella
Abstract: DESCRIPTION (provided by applicant): RNA viruses are a significant cause of morbidity and mortality in humans. Some representatives of this large group of pathogens are hepatitis A, B and C viruses, HIV, influenza virus, most of the cold viruses, rabies virus, Ebola virus, West Nile virus, and dengue virus. We face major difficulties in controlling these viral diseases because of the viruses'escape from immune responses, escape from antiviral drugs, and the emergence of new viruses from animal reservoirs. All these difficulties are caused by the same process: RNA viruses rapidly adapt to new challenges in their environment. This rapid adaptation is possible because RNA virus populations are extremely heterogeneous. Among the variants in a viral population there are usually mutants capable of replicating in the presence of antibodies, antiviral drugs, or in new host cells. New therapies must be designed such that the development of resistance can be prevented or at least substantially delayed. However, we currently have no systematic strategy to develop such therapies, and the predominant approach is trial-and-error. This proposal will continue to build a framework of RNA virus evolution that will be used to develop improved antiviral strategies in a rational way. We use a unique approach of experimental virus evolution (which includes detailed phenotypic and genotypic analyses) combined with computer simulation to address fundamental questions of viral adaptation. We propose to study genetic and environmental determinants that lead to fitness changes and to differences in the potential of a virus population to adapt. Our model system is vesicular stomatitis virus, a well characterized and widely studied virus. We will evaluate three aspects of RNA virus evolution: (i) The genetic basis of differences in adaptability;(ii) the effect of two environmental determinants, population size and population density, on the speed of evolution and the maintenance of variation;and (iii) the consequences of interactions between genetic components and environmental components for virus evolution.
Funding Period: 2005-06-15 - 2010-02-28
more information: NIH RePORT

Top Publications

  1. pmc Antagonistic pleiotropy involving promoter sequences in a virus
    John B Presloid
    Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, 3055 Arlington Avenue, Toledo, OH 43614, USA
    J Mol Biol 382:342-52. 2008
  2. pmc The role of environmental factors on the evolution of phenotypic diversity in vesicular stomatitis virus populations
    Sarah D Smith-Tsurkan
    Department of Medical Microbiology and Immunology, College of Medicine, University of Toledo Health Science Campus, Toledo, OH, USA
    J Gen Virol 94:860-8. 2013
  3. pmc Directional memory and caged dynamics in cytoskeletal remodelling
    Guillaume Lenormand
    Molecular and Integrative Physiological Sciences, Department of Environmental Health, School of Public Health, Harvard University, Boston, MA 02115, USA
    Biochem Biophys Res Commun 360:797-801. 2007
  4. pmc Specific and nonspecific host adaptation during arboviral experimental evolution
    Isabel S Novella
    Department of Medical Microbiology and Immunology, College of Medicine, University of Toledo Health Science Campus, Toledo, Ohio, USA
    J Mol Microbiol Biotechnol 21:71-81. 2011
  5. pmc Does mutational robustness inhibit extinction by lethal mutagenesis in viral populations?
    Eamon B O'Dea
    Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America
    PLoS Comput Biol 6:e1000811. 2010
  6. pmc Detecting positive and purifying selection at synonymous sites in yeast and worm
    Tong Zhou
    Center for Computational Biology and Bioinformatics, University of Texas at Austin, TX, USA
    Mol Biol Evol 27:1912-22. 2010
  7. pmc Genomic evolution of vesicular stomatitis virus strains with differences in adaptability
    Isabel S Novella
    Department of Microbiology and Immunology, University of Toledo Health Science Campus, Mail stop 1210, Toledo, OH 43614, USA
    J Virol 84:4960-8. 2010
  8. pmc Incongruent fitness landscapes, not tradeoffs, dominate the adaptation of vesicular stomatitis virus to novel host types
    Sarah D Smith-Tsurkan
    Department of Medical Microbiology and Immunology, College of Medicine, University of Toledo Health Science Campus, Toledo, OH 43614, USA
    J Gen Virol 91:1484-93. 2010
  9. pmc A linear relationship between fitness and the logarithm of the critical bottleneck size in vesicular stomatitis virus populations
    Isabel S Novella
    Department of Microbiology and Immunology, University of Toledo Health Science Campus, Mail stop 1210, Toledo, OH 43614, USA
    J Virol 82:12589-90. 2008
  10. pmc Lethal mutagenesis of bacteria
    James J Bull
    Institute for Cellular and Molecular Biology, Center for Computational Biology and Bioinformatics, University of Texas, Austin, Texas 78712, USA
    Genetics 180:1061-70. 2008

Scientific Experts

  • C O Wilke
  • Isabel S Novella
  • Ahmad R Sedaghat
  • Nobuto Takeuchi
  • Jesse D Bloom
  • IGOR ROUZINE
  • Dion J Whitehead
  • Tong Zhou
  • Sarah D Smith-Tsurkan
  • Robert Forster
  • D Allan Drummond
  • Eamon B O'Dea
  • Timothy P Brennan
  • Shelby H Steinmeyer
  • James J Bull
  • John B Presloid
  • Ranendra N Dutta
  • Eric Brunet
  • Robert F Siliciano
  • Janet D Siliciano
  • J J Bull
  • Guillaume Lenormand
  • Justin R Bailey
  • Roger A Herr
  • Sadik Khuder
  • Thomas E Keller
  • Wanjun Gu
  • Mason Weems
  • John O Woods
  • Sarah D Smith
  • Bonnie E Ebendick-Corpus
  • Peter J Enyeart
  • Selene Z├írate
  • R Sanjuan
  • James P Butler
  • Jeffrey J Fredberg
  • Julien Chopin
  • Predrag Bursac
  • Deborah Persaud
  • Christoph Adami
  • Joseph Cofrancesco
  • Patricia K Lee
  • Christine M Haggerty
  • Stuart C Ray
  • Jessica Lee
  • Megan Wind-Rotolo
  • Alpan Raval
  • Richard E Nettles
  • Joel E Gallant
  • Yi Liu
  • Tara Kieffer
  • Timothy Brennan
  • Ashrit R Kamireddi
  • Thomas C Quinn

Detail Information

Publications37

  1. pmc Antagonistic pleiotropy involving promoter sequences in a virus
    John B Presloid
    Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, 3055 Arlington Avenue, Toledo, OH 43614, USA
    J Mol Biol 382:342-52. 2008
    ..Mutations involved in fitness tradeoffs included changes in regulatory sequences, particularly at the 3' termini of the genomes, which contain the single promoter that controls viral transcription and replication...
  2. pmc The role of environmental factors on the evolution of phenotypic diversity in vesicular stomatitis virus populations
    Sarah D Smith-Tsurkan
    Department of Medical Microbiology and Immunology, College of Medicine, University of Toledo Health Science Campus, Toledo, OH, USA
    J Gen Virol 94:860-8. 2013
    ..In contrast, environmental heterogeneity, host breadth and the cell type used for testing (as opposed to the cell type used for selection) did not seem to have an effect on the amount of phenotypic diversity observed...
  3. pmc Directional memory and caged dynamics in cytoskeletal remodelling
    Guillaume Lenormand
    Molecular and Integrative Physiological Sciences, Department of Environmental Health, School of Public Health, Harvard University, Boston, MA 02115, USA
    Biochem Biophys Res Commun 360:797-801. 2007
    ..As such, these data are the first to provide a molecular-scale physical picture describing the cytoskeletal remodelling process and its rate of progression...
  4. pmc Specific and nonspecific host adaptation during arboviral experimental evolution
    Isabel S Novella
    Department of Medical Microbiology and Immunology, College of Medicine, University of Toledo Health Science Campus, Toledo, Ohio, USA
    J Mol Microbiol Biotechnol 21:71-81. 2011
    ....
  5. pmc Does mutational robustness inhibit extinction by lethal mutagenesis in viral populations?
    Eamon B O'Dea
    Section of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America
    PLoS Comput Biol 6:e1000811. 2010
    ..We conclude that the evolution of mutational robustness is in most cases unlikely to prevent the extinction of viruses by lethal mutagenesis...
  6. pmc Detecting positive and purifying selection at synonymous sites in yeast and worm
    Tong Zhou
    Center for Computational Biology and Bioinformatics, University of Texas at Austin, TX, USA
    Mol Biol Evol 27:1912-22. 2010
    ..We suggest that the ratio dN/dS(C) may be more appropriate than the ratio dN/dS to identify positive or purifying selection on amino acids...
  7. pmc Genomic evolution of vesicular stomatitis virus strains with differences in adaptability
    Isabel S Novella
    Department of Microbiology and Immunology, University of Toledo Health Science Campus, Mail stop 1210, Toledo, OH 43614, USA
    J Virol 84:4960-8. 2010
    ..We confirmed our hypothesis in mutation-accumulation experiments that showed a normalized fitness loss that was significantly larger in mutant bottlenecked populations than in control populations...
  8. pmc Incongruent fitness landscapes, not tradeoffs, dominate the adaptation of vesicular stomatitis virus to novel host types
    Sarah D Smith-Tsurkan
    Department of Medical Microbiology and Immunology, College of Medicine, University of Toledo Health Science Campus, Toledo, OH 43614, USA
    J Gen Virol 91:1484-93. 2010
    ....
  9. pmc A linear relationship between fitness and the logarithm of the critical bottleneck size in vesicular stomatitis virus populations
    Isabel S Novella
    Department of Microbiology and Immunology, University of Toledo Health Science Campus, Mail stop 1210, Toledo, OH 43614, USA
    J Virol 82:12589-90. 2008
    ....
  10. pmc Lethal mutagenesis of bacteria
    James J Bull
    Institute for Cellular and Molecular Biology, Center for Computational Biology and Bioinformatics, University of Texas, Austin, Texas 78712, USA
    Genetics 180:1061-70. 2008
    ..Implications for the treatment of bacteria with mutagens, for the evolution of mutator strains in bacterial populations, and also for the evolution of mutation rate in cancer are discussed...
  11. pmc The stochastic edge in adaptive evolution
    Eric Brunet
    Laboratoire de Physique Statistique, Ecole Normale Superieure, 75230 Paris Cedex 05, France
    Genetics 179:603-20. 2008
    ..Our results are compatible with predictions made using a different analytical approach (Rouzine et al.) and agree well with numerical simulations...
  12. pmc The look-ahead effect of phenotypic mutations
    Dion J Whitehead
    Institute for Evolution and Biodiversity, The Westphalian Wilhelms University of Muenster, 48149 Muenster, Germany
    Biol Direct 3:18. 2008
    ..The intermediate steps in such evolutionary trajectories are likely to be selectively neutral or deleterious. Therefore, large populations and long times may be required to evolve such traits...
  13. pmc Detecting clusters of mutations
    Tong Zhou
    Center for Computational Biology and Bioinformatics, Section of Integrative Biology, University of Texas at Austin, Austin, Texas, United States of America
    PLoS ONE 3:e3765. 2008
    ..Our algorithm provides a novel method to identify functionally relevant divergence between groups of species. Moreover, it could also be useful to detect artifacts in automatically assembled genomes...
  14. pmc Translationally optimal codons associate with structurally sensitive sites in proteins
    Tong Zhou
    Center for Computational Biology and Bioinformatics, The University of Texas at Austin, TX, USA
    Mol Biol Evol 26:1571-80. 2009
    ..Finally, we find that our results depend weakly on expression level; the association between optimal codons and buried sites exists at all expression levels, but increases in strength as expression level increases...
  15. pmc Constraints on the dominant mechanism for HIV viral dynamics in patients on raltegravir
    Ahmad R Sedaghat
    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
    Antivir Ther 14:263-71. 2009
    ..Alternative explanations for this phenomenon are also possible. For example, the stage in the viral life cycle at which raltegravir acts might explain the distinct viral dynamics produced by this drug...
  16. pmc Analysis of human immunodeficiency virus type 1 viremia and provirus in resting CD4+ T cells reveals a novel source of residual viremia in patients on antiretroviral therapy
    Timothy P Brennan
    Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Virol 83:8470-81. 2009
    ..The finding that some of the residual viremia in patients on HAART stems from an unidentified cellular source other than CD4(+) T cells has implications for eradication efforts...
  17. pmc Lethal mutagenesis in a structured environment
    Shelby H Steinmeyer
    Department of Mathematics, The University of Texas at Austin, Austin, TX 78712, USA
    J Theor Biol 261:67-73. 2009
    ..The smaller R(0), the less migration is necessary to neutralize refugia and the less mutagen is necessary to achieve extinction at high migration rates...
  18. pmc T cell dynamics and the response to HAART in a cohort of HIV-1-infected elite suppressors
    Ahmad R Sedaghat
    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    Clin Infect Dis 49:1763-6. 2009
    ..Interestingly, treatment of an elite suppressor with highly active antiretroviral therapy (HAART) led to a marked decrease in immune activation...
  19. ncbi Contact density affects protein evolutionary rate from bacteria to animals
    Tong Zhou
    Center for Computational Biology and Bioinformatics, Section of Integrative Biology, University of Texas at Austin, Austin, TX 78731, USA
    J Mol Evol 66:395-404. 2008
    ..Our study provides evidence that contact density can increase evolutionary rates, and that it acts similarly on the level of entire proteins and of individual protein domains...
  20. pmc Decay dynamics of HIV-1 depend on the inhibited stages of the viral life cycle
    Ahmad R Sedaghat
    Department of Medicine and Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    Proc Natl Acad Sci U S A 105:4832-7. 2008
    ..We propose that clinically observed viral decay rates for HAART regimens should be evaluated in the context of the drug classes that are represented...
  21. pmc Predicting the tolerance of proteins to random amino acid substitution
    Claus O Wilke
    Keck Graduate Institute of Applied Life Sciences, Claremont, California, USA
    Biophys J 89:3714-20. 2005
    ..We test the accuracy of all approximations against our simulation results, and find good overall agreement between the approximations and the simulation measurements...
  22. ncbi A single determinant dominates the rate of yeast protein evolution
    D Allan Drummond
    Program in Computation and Neural Systems, California Institute of Technology, Pasadena, USA
    Mol Biol Evol 23:327-37. 2006
    ..Our results support the hypothesis that translational selection governs the rate of synonymous and protein sequence evolution in yeast...
  23. ncbi Tradeoff between short-term and long-term adaptation in a changing environment
    Robert Forster
    Digital Life Laboratory, California Institute of Technology, Pasadena, California 91125, USA
    Phys Rev E Stat Nonlin Soft Matter Phys 72:041922. 2005
    ..Our model is relevant for arboviruses, which alternate between different host species on a regular basis...
  24. pmc Population genetics of translational robustness
    Claus O Wilke
    Section of Integrative Biology and Center for Computational Biology and Bioinformatics, University of Texas, Austin 78712, USA
    Genetics 173:473-81. 2006
    ..Here, we study a simple theoretical model of translational robustness that allows us to gain analytic insight into how this paradoxical behavior arises...
  25. pmc Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells
    Justin R Bailey
    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    J Virol 80:6441-57. 2006
    ..The sequences have been deposited in GenBank. The accession numbers are DQ 391282 to DQ 391351 (for env) and DQ 391352 to DQ 392955 (for RT)...
  26. ncbi Structural determinants of the rate of protein evolution in yeast
    Jesse D Bloom
    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, USA
    Mol Biol Evol 23:1751-61. 2006
    ..Our results provide evidence that protein structure plays an important role in shaping the rate of sequence evolution and provide evidence to support recent theoretical advances linking structural designability to contact density...
  27. ncbi Selection for mutational robustness in finite populations
    Robert Forster
    Digital Life Laboratory, California Institute of Technology, Pasadena, CA 91125, USA
    J Theor Biol 243:181-90. 2006
    ..Our results show that quasispecies effects and neutral drift can occur concurrently, and that the relative importance of each is determined by the product of population size and mutation rate...
  28. pmc Thermodynamics of neutral protein evolution
    Jesse D Bloom
    Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA
    Genetics 175:255-66. 2007
    ..All our theoretical predictions are confirmed by simulations with lattice proteins. Our work provides a mathematical foundation for understanding how protein biophysics shapes the process of evolution...
  29. pmc Theory of lethal mutagenesis for viruses
    J J Bull
    Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712, USA
    J Virol 81:2930-9. 2007
    ..We discuss three methods for estimating the former. Estimating the latter is more challenging, but broad limits to this estimate may be feasible...
  30. pmc Error-threshold exists in fitness landscapes with lethal mutants
    Nobuto Takeuchi
    BMC Evol Biol 7:15; author reply 15. 2007
    ..In this article, we study whether the above conclusion holds in high-dimensional genotype space without the assumption of the adjacency of mutations, where the consequences of mutation-selection dynamics can be qualitatively different...
  31. pmc Emergence of mammalian cell-adapted vesicular stomatitis virus from persistent infections of insect vector cells
    Isabel S Novella
    Department of Medical Microbiology and Immunology, Medical University of Ohio, 3055 Arlington Ave, Toledo, OH 43614, USA
    J Virol 81:6664-8. 2007
    ..Periodic acute replication in mammalian cells likely contributed to extending the survival of minority genomes, but these genomes were also found in strictly persistent populations...
  32. pmc Limits on replenishment of the resting CD4+ T cell reservoir for HIV in patients on HAART
    Ahmad R Sedaghat
    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
    PLoS Pathog 3:e122. 2007
    ..Thus, intensification of standard HAART regimens should have minimal effects on the decay of the latent reservoir...
  33. pmc The traveling-wave approach to asexual evolution: Muller's ratchet and speed of adaptation
    Igor M Rouzine
    Department of Molecular Biology and Microbiology, Tufts University, 136 Harrison Avenue, Boston, MA 02111, USA
    Theor Popul Biol 73:24-46. 2008
    ..We predict the adaptation rate to grow logarithmically in the population size until the population size is extremely large...
  34. pmc Low-level HIV-1 replication and the dynamics of the resting CD4+ T cell reservoir for HIV-1 in the setting of HAART
    Ahmad R Sedaghat
    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore Maryland 21205, USA
    BMC Infect Dis 8:2. 2008
    ..However, the mechanism underlying the long half-life of the latent reservoir is unknown. The most likely potential mechanisms are low-level viral replication and the intrinsic stability of latently infected cells...
  35. pmc Rapid adaptive amplification of preexisting variation in an RNA virus
    Ranendra N Dutta
    Department of Medical Microbiology and Immunology, University of Toledo Health Science Campus, Toledo, OH 43614, USA
    J Virol 82:4354-62. 2008
    ..39, 9%, and 0.06%, respectively. The method can be generalized and applied easily to other rapidly evolving microbes, including both asexual microorganisms and those with recombination...
  36. pmc Quasispecies theory in the context of population genetics
    Claus O Wilke
    BMC Evol Biol 5:44. 2005
    ..A number of recent papers have cast doubt on the applicability of the quasispecies concept to virus evolution, and have argued that population genetics is a more appropriate framework to describe virus evolution than quasispecies theory...