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Mutations in hepatitis C virus NS3 protease domain associated with resistance to specific protease inhibitors in antiviral therapy naïve patients

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Abstract

The prevalence of naturally occurring mutations in hepatitis C virus associated with resistance to protease inhibitors in chronically infected patients has not been reported in Brazil. The NS3 serine protease domain was sequenced in 114 therapy-naïve patients infected with subtype 1a (n = 48), 1b (n = 53), or 3a (n = 13). A V36L mutation was observed in 5.6% patients infected with subtype 1b and in all isolates of the 3a subtype, and a T54S mutation was detected in 4.1% of isolates of subtype 1a. In conclusion, the presence of variants carrying mutations associated with resistance to protease inhibitors in therapy-naïve patients may be important for future therapeutic strategies.

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References

  1. Asselah T, Benhamou Y, Marcellin P (2009) Protease and polymerase inhibitors for the treatment of hepatitis C. Liver Int 29:57–67. doi:10.1111/j.1478-3231.2008.01928.x

    Article  PubMed  Google Scholar 

  2. Barbato G, Cicero DO, Nardi MC, Steinkühler C, Cortese R, De Francesco R et al (1999) The solution structure of the N-terminal proteinase domain of the hepatitis C virus (HCV) NS3 protein provides new insights into its activation and catalytic mechanism. J Mol Biol 289:371–384. doi:10.1006/jmbi.1999.2745

    Article  CAS  PubMed  Google Scholar 

  3. Bartels DJ, Zhou Y, Zhang EZ, Marcial M, Byrn RA, Pfeiffer T et al (2008) Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3.4A protease inhibitors in treatment-naive subjects. J Infect Dis 198:800–807. doi:10.1086/591141

    Article  CAS  PubMed  Google Scholar 

  4. Beyer BM, Zhang R, Hong Z, Madison V, Malcolm BA (2001) Effect of naturally occurring active site mutations on hepatitis C virus NS3 protease specificity. Proteins 43:82–88. doi:10.1002/1097-0134(20010501)43:2<82::AID-PROT1020>3.0.CO;2-4

    Article  CAS  PubMed  Google Scholar 

  5. Campiotto S, Pinho JR, Carrilho FJ, Da Silva LC, Souto FJ, Spinelli V et al (2006) Geographic distribution of hepatitis C virus genotypes in Brazil. Braz J Med Biol Res 39:41–49. doi:10.1590/S0100-879X2005000100007

    Google Scholar 

  6. Chase R, Skelton A, Xia E, Curry S, Liu S, McMonagle P et al (2009) A novel HCV NS3 protease mutation selected by combination treatment of the protease inhibitor boceprevir and NS5B polymerase inhibitors. Antiviral Res 84:178–184. doi:10.1016/j.antiviral.2009.09.003

    Article  CAS  PubMed  Google Scholar 

  7. Colson P, Brouk N, Lembo F, Castellani P, Tamalet C, Gérolami R (2008) Natural presence of substitution R155K within hepatitis C virus NS3 protease from a treatment-naïve chronically infected patient. Hepatology 47:766–767. doi:10.1002/hep.22122

    Article  PubMed  Google Scholar 

  8. Flisiak R, Parfieniuk A (2010) Investigational drugs for hepatitis C. Expert Opin Investig Drugs 19:63–75. doi:10.1517/13543780903431034

    Article  CAS  PubMed  Google Scholar 

  9. Fonseca JCF (1999) Epidemiologia da infecção pelo virus da hepatite C no Brasil. Relatório do Grupo de Estudo da Sociedade Brasileira de Hepatologia. GED Gastroenterol Endosc Dig 18(Supl 1):S3–8

  10. Hadziyannis SJ, Sette H, Morgan TR, Balan V, Diago M, Marcellin P et al (2004) Peginterferon alpha 2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 140:346–355

    CAS  PubMed  Google Scholar 

  11. Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK et al (2008) Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients. Hepatology 48:1769–1778. doi:10.1002/hep.22549

    Article  PubMed  Google Scholar 

  12. Lin TI, Lenz O, Fanning G, Verbinnen T, Delouvroy F, Scholliers A et al (2009) In vitro activity and preclinical profile of TMC435350, a potent hepatitis C virus protease inhibitor. Antimicrob Agents Chemother 53:1377–1385. doi:10.1128/AAC.01058-08

    Article  CAS  PubMed  Google Scholar 

  13. López-Labrador FX (2008) Hepatitis C virus NS3/4A protease inhibitors. Recent Pat Antiinfect Drug Discov 3:157–167. doi:10.2174/157489108786242369

    Article  PubMed  Google Scholar 

  14. López-Labrador FX, Moya A, Gonzàlez-Candelas F (2008) Mapping natural polymorphisms of hepatitis C virus NS3/4A protease and antiviral resistance to inhibitors in worldwide isolates. Antivir Ther 13:481–494

    PubMed  Google Scholar 

  15. Lu L, Pilot-Matias TJ, Stewart KD, Randolph JT, Pithawalla R, He W et al (2004) Mutations conferring resistance to a potent hepatitis C virus serine protease inhibitor in vitro. Antimicrob Agents Chemother 48:2260–2266. doi:10.1128/AAC.48.6.2260-2266.2004

    Article  CAS  PubMed  Google Scholar 

  16. Rajagopalan R, Misialek S, Stevens S, Myszka D, Brandhuber B, Ballard J et al (2009) Inhibition and binding kinetics of the hepatitis C virus NS3 protease inhibitor ITMN-191 reveals tight binding and slow dissociative behavior. Biochemistry 48:2559–2568. doi:10.1021/bi900038p

    Article  CAS  PubMed  Google Scholar 

  17. Sarrazin C, Kieffer TL, Bartels D, Hanzelka B, Müh U, Welker M et al (2007) Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 132:1767–1777. doi:10.1053/j.gastro.2007.02.037

    Article  CAS  PubMed  Google Scholar 

  18. Simmonds P (2004) Genetic diversity and evolution of hepatitis C virus—15 years on. J Gen Virol 85:3173–3188. doi:10.1099/vir.0.80401-0

    Article  CAS  PubMed  Google Scholar 

  19. Soriano V, Peters MG, Zeuzem S (2009) New therapies for hepatitis C virus infection. Clin Infect Dis 48:313–320. doi:10.1086/595848

    Article  PubMed  Google Scholar 

  20. Suzuki T, Aizaki H, Murakami K, Shoji I, Wakita T (2007) Molecular biology of hepatitis C virus. J Gastroenterol 42:411–423. doi:10.1007/s00535-007-2030-3

    Article  CAS  PubMed  Google Scholar 

  21. Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol Biol Evol 24:1596–1599. doi: 10.1093/molbev/msm092

    Google Scholar 

  22. Thibeault D, Bousquet C, Gingras R, Lagacé L, Maurice R, White PW et al (2004) Sensitivity of NS3 serine proteases from hepatitis C virus genotypes 2 and 3 to the inhibitor BILN 2061. J Virol 78:7352–7359. doi:10.1128/JVI.78.14.7352-7359.2004

    Article  CAS  PubMed  Google Scholar 

  23. Thompson AJ, McHutchison JG (2009) Antiviral resistance and specifically targeted therapy for HCV (STAT-C). J Viral Hepat 16:377–387. doi:10.1111/j.1365-2893.2009.01124.x

    Article  CAS  PubMed  Google Scholar 

  24. Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25:4876–4882

    Article  CAS  PubMed  Google Scholar 

  25. Welsch C, Domingues FS, Susser S, Antes I, Hartmann C, Mayr G, Schlicker A et al (2008) Molecular basis of telaprevir resistance due to V36 and T54 mutations in the NS3-4A protease of the hepatitis C virus. Genome Biol 9:R16. doi:10.1186/gb-2008-9-1-r16

    Article  PubMed  CAS  Google Scholar 

  26. Yan Y, Li Y, Munshi S, Sardana V, Cole JL, Sardana M et al (1998) Complex of NS3 protease and NS4A peptide of BK strain hepatitis C virus: a 2.2 a resolution structure in a hexagonal crystal form. Protein Sci 7:837–847

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Plataforma Genômica-Sequenciamento de DNA/PDTIS-FIOCRUZ for DNA sequencing and Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq; Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES and to Program Papes V from Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil for financial support.

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  1. Viral Hepatitis Laboratory, Oswaldo Cruz Foundation, FIOCRUZ, Rua Leopoldo Bulhões 1480, Rio de Janeiro, CEP 21041-210, Brazil

    Allan Peres-da-Silva, Adilson José de Almeida & Elisabeth Lampe

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  1. Allan Peres-da-Silva
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  2. Adilson José de Almeida
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  3. Elisabeth Lampe
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Correspondence to Elisabeth Lampe.

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Peres-da-Silva, A., de Almeida, A.J. & Lampe, E. Mutations in hepatitis C virus NS3 protease domain associated with resistance to specific protease inhibitors in antiviral therapy naïve patients. Arch Virol 155, 807–811 (2010). https://doi.org/10.1007/s00705-010-0642-z

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  • DOI: https://doi.org/10.1007/s00705-010-0642-z

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