Skip to main content

NS3 protease resistance-associated substitutions in liver tissue and plasma samples from patients infected by hepatitis C virus genotype 1A or 1B

Archives of Virology volume 162, pages 2271–2277 (2017)Cite this article

Abstract

The presence of naturally occurring resistance-associated substitutions (RASs) in the HCV-protease domain has been poorly investigated in the liver, the main site of HCV replication. We evaluated the natural resistance of the virus to NS3 protease inhibitors in liver tissue and plasma samples taken from HCV-infected patients. RASs were investigated by means of viral population sequencing in liver tissue samples from 18 HCV-infected patients harbouring genotype 1a or genotype 1b; plasma samples from 12 of these patients were also available for virological investigation. A discordant genotype was found in two of the 12 patients (16.6%) who provided samples from both compartments. Sequence analysis of the NS3 protease domain showed the presence of RASs in four of the 18 liver tissue samples (22.2%), two of which showed cross-resistance to protease inhibitors in clinical use or phase 2–3 trials. The analysis of the 12 paired tissues and plasma samples excluded the presence of RASs in the plasma compartment. The dominance of discordant genotypes in the paired liver and plasma samples of some HCV-infected patients suggests mixed infection possibly leading to the selective advantage of different genotype in the two compartments. The presence of RASs at intra-hepatic level is not uncommon and may lead to the early emergence of cross-resistant strains.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Lenz O, Verbinnen T, Fevery B, Tambuyzer L, Vijgen L, Peeters M, Buelens A, Ceulemans H, Beumont M, Picchio G, De Meyer S (2015) Virology analyses of HCV isolates from genotype 1-infected patients treated with simeprevir plus peginterferon/ribavirin in Phase IIb/III studies. J Hepatol 62:1008–1014. doi:10.1016/j.jhep.2014.11.032

    CAS  Article  PubMed  Google Scholar 

  2. Sarrazin C, Lathouwers E, Peeters M, Daems B, Buelens A, Witek J, Wyckmans Y, Fevery B, Verbinnen T, Ghys A, Schlag M, Baldini A, De Meyer S, Lenz O (2015) Prevalence of the hepatitis C virus NS3 polymorphism Q80K in genotype 1 patients in the European region. Antivir Res 116:10–16. doi:10.1016/j.antiviral.2015.01.003

    CAS  Article  PubMed  Google Scholar 

  3. Cuypers L, Li G, Libin P, Piampongsant S, Vandamme AM, Theys K (2015) Genetic diversity and selective pressure in Hepatitis C virus genotypes 1-6: significance for direct-acting antiviral treatment and drug resistance. Viruses 7:5018–5039. doi:10.3390/v7092857

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Maimone S, Musolino C, Squadrito G, Raffa G, Pollicino T, Raimondo G (2013) NS3 genetic variability in HCV genotype-1b isolates from liver specimens and blood samples of treatment-naive patients with chronic hepatitis C. Antivir Ther 18:131–134

    CAS  Article  PubMed  Google Scholar 

  5. Lodrini S, Bagaglio S, Canducci F, De Mitri MS, Andreone P, Loggi E, Lazzarin A, Clementi M, Morsica G (2003) Sequence analysis of NS3 protease gene in clinical strains of hepatitis C virus. J Biol Regul Homeost Agents 17:198–204

    CAS  PubMed  Google Scholar 

  6. Pickett BE, Striker R, Lefkowitz EJ (2011) Evidence for separation of HCV subtype 1a into two distinct clades. J Viral Hepat 18:608–618

    CAS  Article  PubMed  Google Scholar 

  7. Lontok E, Harrington P, Howe A, Kieffer T, Lennerstrand J, Lenz O, McPhee F, Mo H, Parkin N, Pilot-Matias T, Miller V (2015) Hepatitis C virus drug resistance-associated substitutions: state of the art summary. Hepatology 62:1623–1632. doi:10.1002/hep.27934

    Article  PubMed  Google Scholar 

  8. Howe AY, Black S, Curry S, Ludmerer SW, Liu R, Barnard RJ, Newhard W, Hwang PM, Nickle D, Gilbert C, Caro L, Di Nubile MJ, Mobashery N (2014) Virologic resistance analysis from a phase 2 study of MK-5172 combined with pegylated interferon/ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection. Clin Infect Dis 59:1657–1665. doi:10.1093/cid/ciu696

    CAS  Article  PubMed  Google Scholar 

  9. Bagaglio S, Uberti-Foppa C, Di Serio C, Trentini F, Andolina A, Hasson H, Messina E, Merli M, Porrino L, Lazzarin A, Morsica G (2015) Dynamic of mixed HCV infection in plasma and PBMC of HIV/HCV patients under treatment with peg-IFN/Ribavirin. Medicine 94:e1876. doi:10.1097/MD.0000000000001876

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Jamalidoust M, Namayandeh M, Asaei S, Aliabadi N, Ziyaeyan M (2014) Determining hepatitis C virus genotype distribution among high-risk groups in Iran using real-time PCR. World J Gastroenterol 20:5897–5902. doi:10.3748/wjg.v20.i19.5897

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Soriano V, Nedjar S, García-Samaniego J, Bravo R, Castro A, González J, Martínez-Odriozola P, Pedreira J, del Romero J, Suárez D, Llibre JM, Gonzalez-Lahoz J (1995) High rate of co-infection with different hepatitis C virus subtypes in HIV-infected intravenous drug addicts in Spain. Hepatitis HIV Spanish Study Group. J Hepatol 22:598–599

    CAS  Article  PubMed  Google Scholar 

  12. Bagaglio S, Cinque P, Racca S, Pedale R, Grasso MA, Lazzarin A, Morsica G (2005) Hepatitis C virus populations in the plasma, peripheral blood mononuclear cells and cerebrospinal fluid of HIV/hepatitis C virus-co-infected patients. AIDS S3:S151–S165

    Article  Google Scholar 

  13. Cabot B, Esteban JI, Martell M, Genescà J, Vargas V, Esteban R, Guardia J, Gómez J (1997) Structure of replicating hepatitis C virus (HCV) quasispecies in the liver may not be reflected by analysis of circulating HCV virions. J Virol 71:1732–1734

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Han B, Dvory-Sobol H, Greenstein A, McCarville JF, Hung M, Liu X, Miller MD, Mo H (2015) Development and application of a fast, reproducible assay to measure HCV NS3 protease activity using Escherichia coli lysate. J Virol Methods 225:76–86. doi:10.1016/j.jviromet.2015.09.002

    CAS  Article  PubMed  Google Scholar 

  15. Romano KP, Ali A, Aydin C, Soumana D, Ozen A, Deveau LM, Silver C, Cao H, Newton A, Petropoulos CJ, Huang W, Schiffer CA (2012) The molecular basis of drug resistance against hepatitis C virus NS3/4A protease inhibitors. PLoS Pathog 8:e1002832. doi:10.1371/journal.ppat.1002832

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Schinazi R, Halfon P, Marcellin P, Asselah T (2014) HCV direct-acting antiviral agents: the best interferon-free combinations. Liver Int S1:69–78. doi:10.1111/liv.12423

    Article  Google Scholar 

Download references

Author information

Affiliations

  1. IRCCS-San Raffaele Scientific Institute, Milan, Italy

    Giulia Morsica, Andrea Andolina, Marco Merli, Emanuela Messina, Hamid Hasson, Adriano Lazzarin, Caterina Uberti-Foppa & Sabrina Bagaglio

  2. Vita-Salute University, Milan, Italy

    Andrea Andolina, Marco Merli, Emanuela Messina & Adriano Lazzarin

Authors
  1. Giulia Morsica
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrea Andolina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Merli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emanuela Messina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hamid Hasson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adriano Lazzarin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Caterina Uberti-Foppa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sabrina Bagaglio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giulia Morsica.

Ethics declarations

Conflict of interest disclosures

AL has acted as a consultant, participated as a speaker on an advisory board, or participated in conducting clinical trials for Abbott, BMS, Gilead, MSD, ViiV Health, Pfizer, AbbVie. None of the other authors has any conflict of interest to disclose.

Financial support

This study was supported by internal funding from Ospedale San Raffaele, Milan, Italy.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Morsica, G., Andolina, A., Merli, M. et al. NS3 protease resistance-associated substitutions in liver tissue and plasma samples from patients infected by hepatitis C virus genotype 1A or 1B. Arch Virol 162, 2271–2277 (2017). https://doi.org/10.1007/s00705-017-3341-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-017-3341-1

Keywords

  • Liver Tissue Sample
  • Discordant Genotype