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Archives of Virology

, Volume 155, Issue 5, pp 807–811 | Cite as

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

  • Allan Peres-da-Silva
  • Adilson José de Almeida
  • Elisabeth LampeEmail author
Brief Report

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.

Keywords

Sustained Virological Response V170I Substitution Protease Inhibitor Telaprevir 
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.

Notes

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.

References

  1. 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 CrossRefPubMedGoogle Scholar
  2. 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 CrossRefPubMedGoogle Scholar
  3. 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 CrossRefPubMedGoogle Scholar
  4. 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 CrossRefPubMedGoogle Scholar
  5. 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. 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 CrossRefPubMedGoogle Scholar
  7. 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 CrossRefPubMedGoogle Scholar
  8. 8.
    Flisiak R, Parfieniuk A (2010) Investigational drugs for hepatitis C. Expert Opin Investig Drugs 19:63–75. doi: 10.1517/13543780903431034 CrossRefPubMedGoogle Scholar
  9. 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):S3–8Google Scholar
  10. 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 140:346–355PubMedGoogle Scholar
  11. 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 CrossRefPubMedGoogle Scholar
  12. 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 CrossRefPubMedGoogle Scholar
  13. 13.
    López-Labrador FX (2008) Hepatitis C virus NS3/4A protease inhibitors. Recent Pat Antiinfect Drug Discov 3:157–167. doi: 10.2174/157489108786242369 CrossRefPubMedGoogle Scholar
  14. 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 13:481–494PubMedGoogle Scholar
  15. 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 CrossRefPubMedGoogle Scholar
  16. 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 CrossRefPubMedGoogle Scholar
  17. 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 CrossRefPubMedGoogle Scholar
  18. 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 CrossRefPubMedGoogle Scholar
  19. 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 CrossRefPubMedGoogle Scholar
  20. 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 CrossRefPubMedGoogle Scholar
  21. 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. 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 CrossRefPubMedGoogle Scholar
  23. 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 CrossRefPubMedGoogle Scholar
  24. 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 25:4876–4882CrossRefPubMedGoogle Scholar
  25. 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 CrossRefPubMedGoogle Scholar
  26. 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 7:837–847PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Allan Peres-da-Silva
    • 1
  • Adilson José de Almeida
    • 1
  • Elisabeth Lampe
    • 1
    Email author
  1. 1.Viral Hepatitis LaboratoryOswaldo Cruz Foundation, FIOCRUZRio de JaneiroBrazil

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