Genetic and antigenic structural characterization for resistance of echovirus 11 to pleconaril in an immunocompromised patient Free

Abstract

Pleconaril is a capsid inhibitor used previously to treat enterovirus infections. A pleconaril-resistant echovirus 11 (E11) strain was identified before pleconaril treatment was given in an immunocompromised patient. The patient was also treated with intravenous Ig (IVIg) for a long period but remained unresponsive. The pleconaril-resistant strains could not be neutralized , confirming IVIg treatment failure. To identify the basis of pleconaril resistance, genetic and structural analyses were conducted. Analysis of a modelled viral capsid indicated conformational changes in the hydrophobic pocket that could prevent pleconaril docking. Substitutions (V117I, V119M and I188L) in the pleconaril-resistant viruses were found in the pocket region of VP1. Modelling suggested that V119M could confer resistance, most probably due to the protruding sulfate side chain of methionine. Although pleconaril resistance induced in a susceptible E11 clinical isolate was characterized by a different substitution (I183M), resistance was suggested to also result from a similar mechanism, i.e. due to a protruding sulfate side chain of methionine. Our results showed that resistant strains that arise display different markers from those identified and suggest that multiple factors may play a role in pleconaril resistance in patient strains. Based on IVIg treatment failure, we predict that one of these factors could be immune related. Thus, both IVIg and capsid inhibitors target the viral capsid and can induce mutations that can be cross-reactive, enabling escape from both IVIg and the drug. This could limit treatment options and should be investigated further.

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2015-03-01
2024-03-29
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References

  1. Benschop K., Molenkamp R., van der Ham A., Wolthers K., Beld M. 2008a; Rapid detection of human parechoviruses in clinical samples by real-time PCR. J Clin Virol 41:69–74 [View Article][PubMed]
    [Google Scholar]
  2. Benschop K., Thomas X., Serpenti C., Molenkamp R., Wolthers K. 2008b; High prevalence of human parechovirus (HPeV) genotypes in the Amsterdam region and identification of specific HPeV variants by direct genotyping of stool samples. J Clin Microbiol 46:3965–3970 [View Article][PubMed]
    [Google Scholar]
  3. Benschop K., Minnaar R., Koen G., van Eijk H., Dijkman K., Westerhuis B., Molenkamp R., Wolthers K. 2010; Detection of human enterovirus and human parechovirus (HPeV) genotypes from clinical stool samples: polymerase chain reaction and direct molecular typing, culture characteristics, and serotyping. Diagn Microbiol Infect Dis 68:166–173 [View Article][PubMed]
    [Google Scholar]
  4. Groarke J. M., Pevear D. C. 1999; Attenuated virulence of pleconaril-resistant coxsackievirus B3 variants. J Infect Dis 179:1538–1541 [View Article][PubMed]
    [Google Scholar]
  5. Han L. Y., Lin H. H., Li Z. R., Zheng C. J., Cao Z. W., Xie B., Chen Y. Z. 2006; pearls: program for energetic analysis of receptor-ligand system. J Chem Inf Model 46:445–450 [View Article][PubMed]
    [Google Scholar]
  6. Hayden F. G., Herrington D. T., Coats T. L., Kim K., Cooper E. C., Villano S. A., Liu S., Hudson S., Pevear D. C.other authors 2003; Efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: results of 2 double-blind, randomized, placebo-controlled trials. Clin Infect Dis 36:1523–1532 [View Article][PubMed]
    [Google Scholar]
  7. Heinz B. A., Rueckert R. R., Shepard D. A., Dutko F. J., McKinlay M. A., Fancher M., Rossmann M. G., Badger J., 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[PubMed]
    [Google Scholar]
  8. Kawabata T. 2003; matras: a program for protein 3D structure comparison. Nucleic Acids Res 31:3367–3369 [View Article][PubMed]
    [Google Scholar]
  9. Kroneman A., Vennema H., Deforche K., Avoort H. v. d., Peñaranda S., Oberste M. S., Vinjé J., Koopmans M. 2011; An automated genotyping tool for enteroviruses and noroviruses. J Clin Virol 51:121–125 [View Article][PubMed]
    [Google Scholar]
  10. Kumar S., Tamura K., Nei M. 2004; mega3: integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment. Brief Bioinform 5:150–163 [View Article][PubMed]
    [Google Scholar]
  11. Laskowski R. A., Watson J. D., Thornton J. M. 2005; ProFunc: a server for predicting protein function from 3D structure. Nucleic Acids Res 33:Web Server issueW89–W93 [View Article][PubMed]
    [Google Scholar]
  12. Laurie A. T., Jackson R. M. 2005; Q-SiteFinder: an energy-based method for the prediction of protein-ligand binding sites. Bioinformatics 21:1908–1916 [View Article][PubMed]
    [Google Scholar]
  13. Ledford R. M., Patel N. R., Demenczuk T. M., Watanyar A., Herbertz T., Collett M. S., Pevear D. C. 2004; VP1 sequencing of all human rhinovirus serotypes: insights into genus phylogeny and susceptibility to antiviral capsid-binding compounds. J Virol 78:3663–3674 [View Article][PubMed]
    [Google Scholar]
  14. Ledford R. M., Collett M. S., Pevear D. C. 2005; Insights into the genetic basis for natural phenotypic resistance of human rhinoviruses to pleconaril. Antiviral Res 68:135–138 [View Article][PubMed]
    [Google Scholar]
  15. McWilliam Leitch E. C., Harvala H., Robertson I., Ubillos I., Templeton K., Simmonds P. 2009; Direct identification of human enterovirus serotypes in cerebrospinal fluid by amplification and sequencing of the VP1 region. J Clin Virol 44:119–124 [View Article][PubMed]
    [Google Scholar]
  16. McWilliam Leitch E. C., Cabrerizo M., Cardosa J., Harvala H., Ivanova O. E., Kroes A. C., Lukashev A., Muir P., Odoom J.other authors 2010; Evolutionary dynamics and temporal/geographical correlates of recombination in the human enterovirus echovirus types 9, 11, and 30. J Virol 84:9292–9300 [View Article][PubMed]
    [Google Scholar]
  17. Pettersen E. F., Goddard T. D., Huang C. C., Couch G. S., Greenblatt D. M., Meng E. C., Ferrin T. E. 2004; UCSF Chimera – a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612 [View Article][PubMed]
    [Google Scholar]
  18. Pevear D. C., Fancher M. J., Felock P. J., Rossmann M. G., Miller M. S., Diana G., Treasurywala A. M., McKinlay M. A., Dutko F. J. 1989; Conformational change in the floor of the human rhinovirus canyon blocks adsorption to HeLa cell receptors. J Virol 63:2002–2007[PubMed]
    [Google Scholar]
  19. Pevear D. C., Tull T. M., Seipel M. E., Groarke J. M. 1999; Activity of pleconaril against enteroviruses. Antimicrob Agents Chemother 43:2109–2115[PubMed]
    [Google Scholar]
  20. Pevear D. C., Hayden F. G., Demenczuk T. M., Barone L. R., McKinlay M. A., Collett M. S. 2005; Relationship of pleconaril susceptibility and clinical outcomes in treatment of common colds caused by rhinoviruses. Antimicrob Agents Chemother 49:4492–4499 [View Article][PubMed]
    [Google Scholar]
  21. Ramachandran S., Kota P., Ding F., Dokholyan N. V. 2011; Automated minimization of steric clashes in protein structures. Proteins 79:261–270 [View Article][PubMed]
    [Google Scholar]
  22. Reed L. J., Muench H. 1938; A simple method of estimating fifty per cent endpoints. Am J Hyg 27:493–497 [View Article]
    [Google Scholar]
  23. Romero J. R. 2001; Pleconaril: a novel antipicornaviral drug. Expert Opin Investig Drugs 10:369–379 [View Article][PubMed]
    [Google Scholar]
  24. Rotbart H. A. 2002; Treatment of picornavirus infections. Antiviral Res 53:83–98 [View Article][PubMed]
    [Google Scholar]
  25. Rotbart H. A., Webster A. D.Pleconaril Treatment Registry Group 2001; Treatment of potentially life-threatening enterovirus infections with pleconaril. Clin Infect Dis 32:228–235 [View Article][PubMed]
    [Google Scholar]
  26. Schneidman-Duhovny D., Inbar Y., Nussinov R., Wolfson H. J. 2005; PatchDock and SymmDock: servers for rigid and symmetric docking. Nucleic Acids Res 33:Web Server issueW363–W367 [View Article][PubMed]
    [Google Scholar]
  27. Shia K. S., Li W. T., Chang C. M., Hsu M. C., Chern J. H., Leong M. K., Tseng S. N., Lee C. C., Lee Y. C.other authors 2002; Design, synthesis, and structure-activity relationship of pyridyl imidazolidinones: a novel class of potent and selective human enterovirus 71 inhibitors. J Med Chem 45:1644–1655 [View Article][PubMed]
    [Google Scholar]
  28. Simmonds P., Smith D. B. 1999; Structural constraints on RNA virus evolution. J Virol 73:5787–5794[PubMed]
    [Google Scholar]
  29. Stuart A. D., McKee T. A., Williams P. A., Harley C., Shen S., Stuart D. I., Brown T. D., Lea S. M. 2002; Determination of the structure of a decay accelerating factor-binding clinical isolate of echovirus 11 allows mapping of mutants with altered receptor requirements for infection. J Virol 76:7694–7704 [View Article][PubMed]
    [Google Scholar]
  30. Wildenbeest J. G., van den Broek P. J., Benschop K. S., Koen G., Wierenga P. C., Vossen A. C., Kuijpers T. W., Wolthers K. C. 2012; Pleconaril revisited: clinical course of chronic enteroviral meningoencephalitis after treatment correlates with in vitro susceptibility. Antivir Ther 17:459–466 [View Article][PubMed]
    [Google Scholar]
  31. Zhang Y. 2008; I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9:40 [View Article][PubMed]
    [Google Scholar]
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