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Mutations in the NS5A gene of hepatitis C virus subtype 1b and response to peg-IFNα-2a/RBV combination therapy in Azerbaijani patients

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Abstract

Hepatitis C virus (HCV) infection is one of the major causes of chronic liver disease throughout the world. The presence of mutations in different regions of the HCV subtype 1b (HCV-1b) nonstructural 5A (NS5A) gene may be associated with response to interferon therapy. This study evaluated whether amino acid substitutions in the NS5A protein of HCV-1b correlated with response to pegylated interferon alfa-2a (peg-IFNα-2a) and ribavirin (RBV) combination therapy in Azerbaijani patients. From March 2010 to April 2014, a total of 34 chronically HCV-1b-infected Azerbaijani patients were enrolled in this prospective study. After extraction of RNA from plasma specimens, the entire sequences of the NS5A gene of HCV was amplified by reverse transcription nested polymerase chain reaction (RT-nested PCR), and the PCR products were sequenced subsequently. The data that were obtained revealed that there was no correlation between the response to HCV combination therapy and the number of mutations in the NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 regions of HCV. It also was found that changes from isoleucine to valine (I2252 V), aspartic acid to glutamic acid (D2257), arginine to lysine (R2269 K), and arginine to glycine in NS5A-PKRBD and from glycine to glutamic acid (G2379E) in the NS5A-V3 region were not associated with HCV treatment outcome. This study showed that genetic variability in the NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 regions is not a predictive factor of SVR, NR or relapse in HCV genotype1b treated with peg-IFNα-2a/RBV combination therapy.

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References

  1. Bokharaei Salim F, Keyvani H, Amiri A, Jahanbakhsh Sefidi F, Shakeri R, Zamani F (2010) Distribution of different hepatitis C virus genotypes in patients with hepatitis C virus infection. World J Gastroenterol 16(16):2005–2009

    Article  PubMed  Google Scholar 

  2. Jahanbakhsh Sefidi F, Keyvani H, Monavari SH, Alavian SM, Fakhim S, Bokharaei-Salim F (2013) Distribution of hepatitis C virus genotypes in Iranian chronic infected patients. Hepat Mon 13(1):e7991

    Article  PubMed  PubMed Central  Google Scholar 

  3. Poynard T, Yuen MF, Ratziu V, Lai CL (2003) Viral hepatitis C. Lancet 362(9401):2095–2100

    Article  PubMed  CAS  Google Scholar 

  4. Alavian SM, Tabatabaei SV, Keshvari M, Behnava B, Miri SM, Elizee PK et al (2010) Peginterferon alpha-2a and ribavirin treatment of patients with haemophilia and hepatitis C virus infection: a single-centre study of 367 cases. Liver Int 30(8):1173–1180

    Article  PubMed  CAS  Google Scholar 

  5. Namazee N, Sali S, Asadi S, Shafiei M, Behnava B, Alavian SM (2012) Real response to therapy in chronic hepatitis C virus patients: a study from iran. Hepat Mon 12(9):e6151

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bokharaei-Salim F, Keyvani H, Monavari SH, Alavian SM, Fakhim S, Nasseri S (2013) Distribution of Hepatitis C Virus Genotypes among Azerbaijani Patients in Capital City of Iran-Tehran. Hepat Mon 13(9):e13699

  7. Yen YH, Hung CH, Hu TH, Chen CH, Wu CM, Wang JH et al (2008) Mutations in the interferon sensitivity-determining region (nonstructural 5A amino acid 2209-2248) in patients with hepatitis C-1b infection and correlating response to combined therapy of pegylated interferon and ribavirin. Aliment Pharmacol Ther 27(1):72–79

    Article  PubMed  CAS  Google Scholar 

  8. Hofmann WP, Zeuzem S, Sarrazin C (2005) Hepatitis C virus-related resistance mechanisms to interferon alpha-based antiviral therapy. J Clin Virol 32(2):86–91

    Article  PubMed  CAS  Google Scholar 

  9. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C et al (1996) Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 334(2):77–81

    Article  PubMed  CAS  Google Scholar 

  10. Chayama K, Tsubota A, Kobayashi M, Okamoto K, Hashimoto M, Miyano Y et al (1997) Pretreatment virus load and multiple amino acid substitutions in the interferon sensitivity-determining region predict the outcome of interferon treatment in patients with chronic genotype 1b hepatitis C virus infection. Hepatology 25(3):745–749

    Article  PubMed  CAS  Google Scholar 

  11. Kurosaki M, Enomoto N, Murakami T, Sakuma I, Asahina Y, Yamamoto C et al (1997) Analysis of genotypes and amino acid residues 2209 to 2248 of the NS5A region of hepatitis C virus in relation to the response to interferon-beta therapy. Hepatology 25(3):750–753

    Article  PubMed  CAS  Google Scholar 

  12. Zeuzem S, Lee JH, Roth WK (1997) Mutations in the nonstructural 5A gene of European hepatitis C virus isolates and response to interferon alfa. Hepatology 25(3):740–744

    Article  PubMed  CAS  Google Scholar 

  13. Murphy MD, Rosen HR, Marousek GI, Chou S (2002) Analysis of sequence configurations of the ISDR, PKR-binding domain, and V3 region as predictors of response to induction interferon-alpha and ribavirin therapy in chronic hepatitis C infection. Dig Dis Sci 47(6):1195–1205

    Article  PubMed  CAS  Google Scholar 

  14. Gale MJ Jr, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE et al (1997) Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 230(2):217–227

    Article  PubMed  CAS  Google Scholar 

  15. Pflugheber J, Fredericksen B, Sumpter R Jr, Wang C, Ware F, Sodora DL et al (2002) Regulation of PKR and IRF-1 during hepatitis C virus RNA replication. Proc Natl Acad Sci USA 99(7):4650–4655

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Honda K, Yanai H, Negishi H, Asagiri M, Sato M, Mizutani T et al (2005) IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434(7034):772–777

    Article  PubMed  CAS  Google Scholar 

  17. Gale M Jr, Blakely CM, Kwieciszewski B, Tan SL, Dossett M, Tang NM et al (1998) Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol 18(9):5208–5218

    PubMed  CAS  PubMed Central  Google Scholar 

  18. Macquillan GC, Niu X, Speers D, English S, Garas G, Harnett GB et al (2004) Does sequencing the PKRBD of hepatitis C virus NS5A predict therapeutic response to combination therapy in an Australian population? J Gastroenterol Hepatol 19(5):551–557

    Article  PubMed  CAS  Google Scholar 

  19. Sarrazin C, Berg T, Lee JH, Ruster B, Kronenberger B, Roth WK et al (2000) Mutations in the protein kinase-binding domain of the NS5A protein in patients infected with hepatitis C virus type 1a are associated with treatment response. J Infect Dis 181(2):432–441

    Article  PubMed  CAS  Google Scholar 

  20. Sarrazin C, Herrmann E, Bruch K, Zeuzem S (2002) Hepatitis C virus nonstructural 5A protein and interferon resistance: a new model for testing the reliability of mutational analyses. J Virol 76(21):11079–11090

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Jabbari H, Bayatian A, Sharifi AH, Zaer-Rezaee H, Fakharzadeh E, Asadi R et al (2010) Safety and efficacy of locally manufactured pegylated interferon in hepatitis C patients. Arch Iran Med 13(4):306–312

    PubMed  CAS  Google Scholar 

  22. Poordad FF, Flamm SL (2009) Virological relapse in chronic hepatitis C. Antivir Ther 14(3):303–313

    PubMed  CAS  Google Scholar 

  23. Bokharaei-Salim F, Keyvani H, Monavari SH, Alavian SM, Madjd Z, Toosi MN et al (2011) Occult hepatitis C virus infection in Iranian patients with cryptogenic liver disease. J Med Virol 83(6):989–995

    Article  PubMed  Google Scholar 

  24. Keyvani H, Bokharaei-Salim F, Monavari SH, Esghaei M, Nassiri Toosi M, Fakhim S et al (2013) Occult hepatitis C virus infection in candidates for liver transplant with cryptogenic cirrhosis. Hepat Mon 13(8):e11290

    Article  PubMed  PubMed Central  Google Scholar 

  25. Pohjanpelto P, Lappalainen M, Widell A, Asikainen K, Paunio M (1996) Hepatitis C genotypes in Finland determined by RFLP. Clin Diagn Virol 7(1):7–16

    Article  PubMed  CAS  Google Scholar 

  26. Munoz de Rueda P, Casado J, Paton R, Quintero D, Palacios A, Gila A et al (2008) Mutations in E2-PePHD, NS5A-PKRBD, NS5A-ISDR, and NS5A-V3 of hepatitis C virus genotype 1 and their relationships to pegylated interferon-ribavirin treatment responses. J Virol 82(13):6644–6653

    Article  PubMed  CAS  Google Scholar 

  27. Farahani M, Bokharaei-Salim F, Ghane M, Basi A, Meysami P, Keyvani H (2013) Prevalence of occult hepatitis C virus infection in Iranian patients with lymphoproliferative disorders. J Med Virol 85(2):235–240

    Article  PubMed  CAS  Google Scholar 

  28. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T et al (2010) Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 138(4):1338–1345 45 e1–7

    Article  PubMed  CAS  Google Scholar 

  29. Sharafi H, Pouryasin A, Alavian SM, Behnava B, Keshvari M, Salimi S et al (2012) Distribution of IL28B Genotypes in Iranian Patients with Chronic Hepatitis C and Healthy Individuals. Hepat Mon 12(12):e8387

    Article  PubMed  PubMed Central  Google Scholar 

  30. Kohashi T, Maekawa S, Sakamoto N, Kurosaki M, Watanabe H, Tanabe Y et al (2006) Site-specific mutation of the interferon sensitivity-determining region (ISDR) modulates hepatitis C virus replication. J Viral Hepat 13(9):582–590

    Article  PubMed  CAS  Google Scholar 

  31. Kmieciak D, Kruszyna L, Migdalski P, Lacinski M, Juszczyk J, Trzeciak WH (2006) Mutations within protein kinase R-binding domain of NS5A protein of hepatitis C virus (HCV) and specificity of HCV antibodies in pretreatment sera of HCV-chronically infected patients and their effect on the result of treatment. Jpn J Infect Dis 59(2):92–99

    PubMed  CAS  Google Scholar 

  32. Brillet R, Penin F, Hezode C, Chouteau P, Dhumeaux D, Pawlotsky JM (2007) The nonstructural 5A protein of hepatitis C virus genotype 1b does not contain an interferon sensitivity-determining region. J Infect Dis 195(3):432–441

    Article  PubMed  CAS  Google Scholar 

  33. Squadrito G, Leone F, Sartori M, Nalpas B, Berthelot P, Raimondo G et al (1997) Mutations in the nonstructural 5A region of hepatitis C virus and response of chronic hepatitis C to interferon alfa. Gastroenterology 113(2):567–572

    Article  PubMed  CAS  Google Scholar 

  34. Hofgartner WT, Polyak SJ, Sullivan DG, Carithers RL Jr, Gretch DR (1997) Mutations in the NS5A gene of hepatitis C virus in North American patients infected with HCV genotype 1a or 1b. J Med Virol 53(2):118–126

    Article  PubMed  CAS  Google Scholar 

  35. Sarrazin C, Berg T, Lee JH, Teuber G, Dietrich CF, Roth WK et al (1999) Improved correlation between multiple mutations within the NS5A region and virological response in European patients chronically infected with hepatitis C virus type 1b undergoing combination therapy. J Hepatol 30(6):1004–1013

    Article  PubMed  CAS  Google Scholar 

  36. Berg T (2000) Mas Marques A, Hohne M, Wiedenmann B, Hopf U, Schreier E. Mutations in the E2-PePHD and NS5A region of hepatitis C virus type 1 and the dynamics of hepatitis C viremia decline during interferon alfa treatment. Hepatology 32(6):1386–1395

    Article  PubMed  CAS  Google Scholar 

  37. Kumthip K, Pantip C, Chusri P, Thongsawat S, O’Brien A, Nelson KE et al (2011) Correlation between mutations in the core and NS5A genes of hepatitis C virus genotypes 1a, 1b, 3a, 3b, 6f and the response to pegylated interferon and ribavirin combination therapy. J Viral Hepat 18(4):e117–e125

    Article  PubMed  CAS  Google Scholar 

  38. Howell CD, Dowling TC, Paul M, Wahed AS, Terrault NA, Taylor M et al (2008) Peginterferon pharmacokinetics in African American and Caucasian American patients with hepatitis C virus genotype 1 infection. Clin Gastroenterol Hepatol 6(5):575–583

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Nousbaum J, Polyak SJ, Ray SC, Sullivan DG, Larson AM, Carithers RL Jr et al (2000) Prospective characterization of full-length hepatitis C virus NS5A quasispecies during induction and combination antiviral therapy. J Virol 74(19):9028–9038

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Yahoo N, Sabahi F, Shahzamani K, Malboobi MA, Jabbari H, Sharifi H et al (2011) Mutations in the E2 and NS5A regions in patients infected with hepatitis C virus genotype 1a and their correlation with response to treatment. J Med Virol 83(8):1332–1337

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by Research Deputy of Iran University of Medical Sciences, grant number 15927.

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The authors have no conflict(s) of interest.

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Correspondence to Hossein Keyvani.

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Bokharaei-Salim, F., Keyvani, H., Salehi-Vaziri, M. et al. Mutations in the NS5A gene of hepatitis C virus subtype 1b and response to peg-IFNα-2a/RBV combination therapy in Azerbaijani patients. Arch Virol 159, 2893–2899 (2014). https://doi.org/10.1007/s00705-014-2133-0

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  • DOI: https://doi.org/10.1007/s00705-014-2133-0

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