Skip to main content

Advertisement

Log in

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

  • Brief Report
  • Published:
Archives of Virology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Elisabeth Lampe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Keywords

Navigation