Variability of the HCV core region and host genetic and epigenetic factors can predict the response to pegylated interferon/ribavirin therapy in genotype 1b hepatitis C patients from Serbia

Authors

  • Nikola S. Kokanov Vinča Institute of Nuclear Sciences – National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade, Serbia https://orcid.org/0000-0002-2380-2028
  • Snežana P. Jovanović-Ćupić Vinča Institute of Nuclear Sciences – National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade, Serbia https://orcid.org/0000-0002-3389-7278
  • Marina M. Šiljić Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia https://orcid.org/0000-0002-5250-1953
  • Valentina S. Ćirković Group for Medical Entomology, Centre of Excellence for Food and Vector Borne Zoonoses, Institute for Medical Research, University of Belgrade, 11000 Belgrade, Serbia https://orcid.org/0000-0003-0453-5945
  • Nina M. Petrović Vinča Institute of Nuclear Sciences – National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade, Serbia https://orcid.org/0000-0003-2503-1228
  • Bojana R. Kožik Vinča Institute of Nuclear Sciences – National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade, Serbia https://orcid.org/0000-0002-2983-4151
  • Milena M. Krajnović Vinča Institute of Nuclear Sciences – National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade, Serbia https://orcid.org/0000-0001-5638-2042

DOI:

https://doi.org/10.2298/ABS230316020K

Keywords:

hepatitis C virus, variability of HCV core region, IL28B, RASSF1A and p16 methylation, therapy response

Abstract

Paper description:

  • Variations in the hepatitis C virus core sequence are related to the progression of liver fibrosis and response to therapy.
  • We previously showed that host genetic and epigenetic factors affect the response to pegylated interferon/ribavirin therapy. Herein we examine whether amino acid substitutions in the HCV core region have similar effects on therapy outcome and disease progression.
  • Patients with amino acid substitution at position 75 and CT/TT IL28B genotype were non-responders. Patients with amino acid substitution at position 91 and CC IL28B genotype had a sustained virologic response.
  • Variability in the HCV core protein may help in predicting treatment response.

Abstract: Variations in the hepatitis C virus (HCV) core sequence have been related to disease progression and response to antiviral therapy. Previously we showed that the methylation status of RASSF1A and p16 genes, and IL28B genotypes affects the response to pegylated interferon/ribavirin (PEG-IFN/RBV) therapy. Herein we investigated whether amino acid (aa) substitutions in the HCV core region alone or in combination with IL28B genotypes and RASSF1A/p16 methylation affect the response to PEG-IFN/RBV therapy and liver disease progression. Among 29 examined patients, we found no association between single aa substitutions and response to therapy. However, we observed that patients with the HCV core aa substitution at position 75 and CT/TT IL28B genotypes were non-responders (NR), (P=0.023). Moreover, these patients had unmethylated RASSF1A. In contrast, most patients (75%) with aa substitutions at position 91 and CC IL28B genotype achieved sustained virologic response (SVR), (P=0.030), and 70% of them had methylated RASSF1A gene. Our results suggest that combined analysis of aa substitutions in the core protein, the IL28B rs12979860 polymorphism, and the methylation status of the RASSF1A gene may help in predicting treatment response to PEG-IFN/RBV in genotype 1b chronic hepatitis C patients.

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References

Dore GJ, Bajis S. Hepatitis C Virus Elimination: Laying the Foundation for Achieving 2030 Targets. Nat Rev Gastroenterol Hepatol. 2021;18(2):91-2. https://doi.org/10.1038/s41575-020-00392-3

Westbrook RH, Dusheiko G. Natural History of Hepatitis C. J Hepatol. 2014;61(1):S58-68. https://doi.org/10.1016/j.jhep.2014.07.012

Petruzziello A, Marigliano S, Loquercio G, Cozzolino A, Cacciapuoti C. Global Epidemiology of Hepatitis C Virus Infection: An Update of the Distribution and Circulation of Hepatitis C Virus Genotypes. World J Gastroenterol. 2016;22(34):7824-40. https://doi.org/10.3748/wjg.v22.i34.7824

Babić JS, Bojović K, Fabri M, Cvejić T, Svorcan P, Nožić D, Jovanović M, Škrbić R, Stojiljković MP, Mijailović Ž. Real-Life Data on the Efficacy and Safety of Ombitasvir/Paritaprevir//Ritonavir+ Dasabuvir+ Ribavirin in the Patients with Genotype 1 Chronic Hepatitis C Virus Infection in Serbia. Vojnosanitetski pregled. 2019;76(5):531-6. https://doi.org/10.2298/VSP170727186S

Raimondi S, Bruno S, Mondeli MU, Maisonneuve. Hepatitis C Virus Genotype 1b as a Risk Factor for Hepatocellular Carcinoma Development: a Meta-Analysis. J Hepatol. 2009;50:1142-54. https://doi.org/10.1016/j.jhep.2009.01.019

Campos LB, de Almeida NA, de Santana CG, Barbosa EN, Horta MA, Amendola Pires M, Brandão Mello CE, de Paula VS, de Barros JJ. Before Direct-Acting Antivirals for Hepatitis C Virus: Evaluation of Core Protein R70Q and L/C91M Substitutions in Chronically Infected Brazilian Patients Unresponsive to IFN and/or RBV. Viruses. 2023;15(1):187. https://doi.org/10.3390/v15010187

Wahid B, Rafique S, Saleem K, Ali A, Idrees M. An Increase in Expression of SOCS1 Gene with Increase in Hepatitis C Virus Viral Load. J Interferon Cytokine Res. 2018;38(3):122-8. https://doi.org/10.1089/jir.2017.0129

Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V, Müller T, Bahlo M, Stewart GJ, Booth DR, George J. IL28B is Associated with Response to Chronic Hepatitis C Interferon-Alpha and Ribavirin Therapy. Nat Genet. 2009;41:1100-4. https://doi.org/10.1038/ng.447

Sugiyama M, Tanaka Y, Nakanishi M, Mizokami M. Novel Findings for the Development of Drug Therapy for Various Liver Diseases: Genetic Variation in IL-28B is Associated with Response to the Therapy for Chronic Hepatitis C. J Pharmacol Sci. 2011;115:263‐9. https://doi.org/10.1254/jphs.10R15FM

Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB. Genetic Variation in IL28B Predicts Hepatitis C Treatment-Induced Viral Clearance. Nature. 2009;461:399‐401. https://doi.org/10.1038/nature08309

Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM. IL-28, IL-29 and Their Class II Cytokine Receptor IL-28R. Nat Immunol. 2003;4(1):63-8. https://doi.org/10.1038/ni873

Jovanović-Ćupić S, Petrovic N, Krajnović M, Bundalo M, Kokanov N, Božović A, Stamenković G. Role of Host and Viral Factors and Genetic Variation of IL28B on Therapy Outcome in Patients with Chronic Hepatitis C Genotype 1b from Serbia. Genetics & Applications. 2019;3(1):36-41. https://doi.org/10.31383/ga.vol3iss1pp36-41

Goto K, Roca Suarez AA, Wrensch F, Baumert TF, Lupberger J. Hepatitis C Virus and Hepatocellular Carcinoma: When the Host Loses Its Grip. Int J Mol Sci. 2020;21(9):3057. https://doi.org/10.3390/ijms21093057

Lim JS, Park SH, Jang KL. Hepatitis C Virus Core Protein Overcomes Stress-Induced Premature Senescence by Down-Regulating p16 Expression via DNA Methylation. Cancer Lett. 2012;321(2):154-61. https://doi.org/10.1016/j.canlet.2012.01.044

Devi P, Ota S, Punga T, Bergqvist A. Hepatitis C Virus Core Protein Down-Regulates Expression of Src-Homology 2 Domain Containing Protein Tyrosine Phosphatase by Modulating Promoter DNA Methylation. Viruses. 2021;13(12):2514. https://doi.org/10.3390/v13122514

Wang X, Zhou Y, Wang C, Zhao Y, Cheng Y, Yu S, Li X, Zhang W, Zhang Y, Quan H. HCV Core Protein Represses DKK3 Expression via Epigenetic Silencing and Activates the Wnt/β-Catenin Signaling Pathway During the Progression of HCC. Clin Transl Oncol. 2022;24(10):1998-2009. https://doi.org/10.1007/s12094-022-02859-y

N Zekri AR, Raafat AM, Elmasry S, et al. Promotor Methylation: Does It Affect Response to Therapy in Chronic Hepatitis C (G4) or Fibrosis? Ann Hepatol. 2014;13:518‐24. https://doi.org/10.1016/S1665-2681(19)31251-7

Mostafa WSEM, Al-Dahr MHS, Omran DAH, Abdullah ZF, Elmasry SH, Ibrahim MN. Influence of Some Methylated Hepatocarcinogenesis-Related Genes on the Response to Antiviral Therapy and Development of Fibrosis in Chronic Hepatitis C Patients. Clin Mol Hepatol. 2020;26:60‐9. https://doi.org/10.3350/cmh.2019.0051

Kokanov N, Krajnović MM, Jovanović-Ćupić SP, Kožik B, Petrović N, Božović AM, Mandušić V. RASSF1A and p16 Promoter Methylation and Treatment Response in Chronic Hepatitis C Genotype 1b Patients Treated with Pegylated Interferon/Ribavirin. Arch Biol Sci. 2022;74(1):57-66. https://doi.org/10.2298/ABS211208004K

Dubois F, Bergot E, Zalcman G, Levallet G. RASSF1A, Puppeteer of Cellular Homeostasis, Fights Tumorigenesis, and Metastasis-an Updated Review. Cell Death Dis. 2019;10:928. https://doi.org/10.1038/s41419-019-2169-x

Rocco JW, Sidransky D. p16(MTS-1/CDKN2/INK4a) in Cancer Progression. Exp Cell Res. 2001;264(1):42‐55. https://doi.org/10.1006/excr.2000.5149

Zang JJ, Xie F, Xu JF, Qin YY, Shen RX, Yang JM, He J. P16 Gene Hypermethylation and Hepatocellular Carcinoma: a Systematic Review and Meta-Analysis. World J Gastroenterol. 2011;17:3043‐8. https://doi.org/10.3748/wjg.v17.i25.3043

Mohamed NA, Swify EM, Amin NF, Soliman MM, Tag-Eldin LM, Elsherbiny NM. Is Serum Level of Methylated RASSF1A Valuable in Diagnosing Hepatocellular Carcinoma in Patients with Chronic Viral Hepatitis C? Arab J Gastroenterol. 2012;13:111‐5. https://doi.org/10.1016/j.ajg.2012.06.009

Guo N, Chen R, Li Z, Liu Y, Cheng D, Zhou Q, Zhou J, Lin Q. Hepatitis C Virus Core Upregulates the Methylation Status of the RASSF1A Promoter Through Regulation of SMYD3 in Hilar Cholangiocarcinoma Cells. Acta Biochim Biophys Sin (Shanghai). 2011;43(5):354-61. https://doi.org/10.1093/abbs/gmr021

Park SH, Lim JS, Lim SY, Tiwari I, Jang KL. Hepatitis C Virus Core Protein Stimulates Cell Growth by Down- Regulating p16 Expression via DNA Methylation. Cancer Lett. 2011;310(1):61-8. https://doi.org/10.1016/j.canlet.2011.06.012

Kittlesen DJ, Chianese-Bullock KA, Yao ZQ, Braciale TJ, Hahn YS. Interaction Between Complement Receptor gC1qR and Hepatitis C Virus Core Protein Inhibits T-lymphocyte Proliferation. J Clin Invest. 2000;106(10):1239-49. https://doi.org/10.1172/JCI10323

Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S. Amino Acid Substitution in Hepatitis C Virus Core Region and Genetic Variation Near the Interleukin 28B Gene Predict Viral Response to Telaprevir with Peginterferon and Ribavirin. Hepatology. 2010;52(2):421-9. https://doi.org/10.1002/hep.23690

Valenti L, Pulixi E, La Spina S. IL28B, HCV Core Mmutations, and Hepatocellular Carcinoma: Does Host Genetic Make-Up Shape Viral Evolution in Response to Immunity? Hepatol Int. 2012;6(1):356-9. https://doi.org/10.1007/s12072-011-9327-2

El-Shamy A, Kim SR, Ide YH, Sasase N, Imoto S, Deng L, Shoji I, Hotta H. Polymorphisms of Hepatitis C Virus Non-Structural Protein 5A and Core Protein and Clinical Ooutcome of Pegylated-Interferon/Ribavirin Combination Therapy. Intervirology. 2012;55(1):1-1. https://doi.org/10.1159/000322219

El-Shamy A, Pendleton M, Eng FJ, Doyle EH, Bashir A, Branch AD. Impact of HCV Core Gene Quasispecies on Hepatocellular Carcinoma Risk Among HALT-C Trial Patients. Sci Rep. 2016;6(1): 27025. https://doi.org/10.1038/srep27025

Akuta N, Suzuki F, Sezaki H, Kobayashi M, Fujiyama S, Kawamura Y, Hosaka T, Kobayashi M, Saitoh S, Suzuki Y, Arase Y. Complex Association of Virus and Host-Related Factors with Hepatocellular Carcinoma Rate Following Hepatitis C Virus Clearance. J Clin Microbiol. 2019;57(1):e01463-18. https://doi.org/10.1128/JCM.01463-18

Okanoue T, Itoh Y, Hashimoto H, Yasui K, Minami M, Takehara T, Tanaka E, Onji M, Toyota J, Chayama K, Yoshioka K, Izumi N, Akuta N, Kumada H. Predictive Values of Amino Acid Sequences of the Core and NS5A Regions in Antiviral Therapy for Hepatitis C: a Japanese Multi-Center Study. J Gastroenterol. 2009;44:952-63. https://doi.org/10.1007/s00535-009-0087-x

Sultana C, Oprişan G, Teleman MD, Dinu S, Oprea C, Voiculescu M, Ruta S. Impact of Hepatitis C Virus Core Mutations on the Response to Interferon-Based Treatment in Chronic Hepatitis C. World J Gastroenterol. 2016;22(37):8406-13. https://doi.org/10.3748/wjg.v22.i37.8406

Dehghani B, Hashempour T, Hasanshahi Z, Moayedi J. Bioinformatics Analysis of Domain 1 of HCV-Core Protein: Iran. Int J Pept Res Ther. 2020;26(1):303-20. https://doi.org/10.1007/s10989-019-09838-y

Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K. Amino Acid Substitutions in the Hepatitis C Virus Core Region are the Important Predictor of Hepatocarcinogenesis. Hepatology. 2007;46(5):1357-64. https://doi.org/10.1002/hep.21836

Nakamoto S, Imazeki F, Fukai K, Fujiwara K, Arai M, Kanda T, Yonemitsu Y, Yokosuka O. Association Between Mutations in the Core Region of Hepatitis C Virus Genotype 1 and Hepatocellular Carcinoma Development. J Hepatol. 2010;52(1):72-8. https://doi.org/10.1016/j.jhep.2009.10.001

Hashempour T, Dehghani B, Musavi Z, Moayedi J, Hasanshahi Z, Sarvari J, Hosseini SY, Hosseini E, Moeini M, Merat S. Impact of IL28 Genotypes and Modeling the Interactions of HCV Core Protein on Treatment of Hepatitis C. Interdiscip Sci. 2020;12(4):424-37. https://doi.org/10.1007/s12539-020-00382-8

Hayes CN, Zhang P, Zhang Y, Chayama K. Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection. Viruses. 2018;10(10):531. https://doi.org/10.3390/v10100531

Bedossa P, Poynard T. An Algorithm for the Grading of Activity in Chronic Hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24:289-93. https://doi.org/10.1002/hep.510240201

Okamoto H, Sugiyama Y, Okada S, Kurai K, Akahane Y, Sugai Y, Tanaka T, Sato K, Tsuda F, Miyakawa Y, Mayumi M. Typing Hepatitis C Virus by Polymerase Chain Reaction with Type-Specific Primers: Application to Clinical Surveys and Tracing Infectious Sources. J Gen Virol. 1992;73:673-9. https://doi.org/10.1099/0022-1317-73-3-673

Okamoto H, Mishiro S. Genetic Heterogeneity of Hepatitis C Virus. Intervirology. 1994;37:68-76. https://doi.org/10.1159/000150360

Nagayama K, Kurosaki M, Enomoto N, Miyasaka Y, Marumo F, Sato C. Characteristics of Hepatitis C Viral Genome Associated with Disease Progression. Hepatology. 2000;31:745-50. https://doi.org/10.1002/hep.510310327

Takahashi K, Iwata K, Matsumoto M, Matsumoto H, Nakao K, Hatahara T, Ohta Y, Kanai K, Maruo H, Baba K, Hijikata M. Hepatitis C Virus (HCV) Genotype 1b Sequences from Fifteen Patients with Hepatocellular Carcinoma: the 'Progression Score' Revisited. Hepatol Res. 2001;20(2):161-71. https://doi.org/10.1016/S1386-6346(00)00141-8

Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H. Amino Acid Substitution in Hepatitis C Virus Core Region and Genetic Variation near the Interleukin 28B Gene Predict Viral Response to Telaprevir with Peginterferon and Ribavirin. Hepatology. 2010;52(2):421-9. https://doi.org/10.1002/hep.23690

Alestig E, Arnholm B, Eilard A, Lagging M, Nilsson S, Norkrans G, Wahlberg T, Wejstål R, Westin J, Lindh M. Core Mutations, IL28B Polymorphisms and Response to Peginterferon/Ribavirin Treatment in Swedish Patients with Hepatitis C Virus Genotype 1 Infection. BMC Infect Dis. 2011;11(1):1-7. https://doi.org/10.1186/1471-2334-11-124

Khan A, Nawaz M, Ullah S, Rehman IU, Khan A, Saleem S, Zaman N, Shinwari ZK, Ali M, Wei DQ. Core Amino Acid Substitutions in HCV-3a Isolates from Pakistan and Opportunities for Multi-Epitopic Vaccines. J Biomol Struct Dyn. 2022;40(8):3753-68. https://doi.org/10.1080/07391102.2020.1850353

Fukuhara T, Takeishi K, Toshima T, Morita K, Ueda S, Iguchi T, Nagata S, Sugimachi K, Ikegami T, Gion T, Soejima Y. Impact of Amino Acid Substitutions in the Core Region of HCV on Multistep Hepatocarcinogenesis. Hepatol Res. 2010;40(2):171-8. https://doi.org/10.1111/j.1872-034X.2009.00575.x

Alhamlan FS, Al-Ahdal MN, Khalaf NZ, Abdo AA, Sanai FM, Al-Ashgar HI, ElHefnawi M, Zaid A, Al-Qahtani AA. Genetic Variability of the Core Protein in Hepatitis C Virus Genotype 4 in Saudi Arabian Patients and Its Implication on Pegylated Interferon and Ribavirin Therapy. J Transl Med. 2014;12(1):1-8. https://doi.org/10.1186/1479-5876-12-91

Pavón-Castillero EJ, Muñoz-de-Rueda P, López-Segura R, Gila A, Quiles R, Muñoz-Gámez JA, Carazo A, Martínez P, Ruiz-Extremera A, Salmerón J. Importance of IL-10 and IL-6 During Chronic Hepatitis C Genotype-1 Treatment and Their Relation with IL28B. Cytokine. 2013;61:595-601. https://doi.org/10.1016/j.cyto.2012.10.009

Yi M, Wang W, Chen S, Peng Y, Li J, Cai J, Zhou Y, Peng Q, Ban Y, Zeng Z, Li X, Xiong W, Li G, Xiang B. Dual-Functionality of RASSF1A Overexpression in A375 Cells is Mediated by Activation of IL-6/STAT3 Regulatory Loop. Mol Biol Rep. 2018;45:1277-87. https://doi.org/10.1007/s11033-018-4288-3

Nishikawa Y, Kajiura Y, Lew JH, Kido JI, Nagata T, Naruishi K. Calprotectin Induces IL-6 and MCP-1 Production via Toll-Like Receptor 4 Signaling in Human Gingival Fibroblasts. J Cell Physiol. 2017;232:1862-71. https://doi.org/10.1002/jcp.25724

Lu H, Han M, Yuan X, Tursun K, Zhang Y, Li Y, Li Z, Feng S, Zhou L, Pan Z, Wang Q, Han K, Liu S, Cheng J. Role of IL-6-Mediated Expression of NS5ATP9 in Autophagy of Liver Cancer Cells. J Cell Physiol. 2018;233:9312-9. https://doi.org/10.1002/jcp.26343

Uraki S, Tameda M, Sugimoto K, Shiraki K, Takei Y, Nobori T, Ito M. Substitution in Amino Acid 70 of Hepatitis C Virus Core Protein Changes the Adipokine Profile via Toll-Like Receptor 2/4 Signaling. PloS one. 2015;10(6):e0131346. https://doi.org/10.1371/journal.pone.0131346

Ogata F, Akuta N, Kobayashi M, Fujiyama S, Kawamura Y, Sezaki H, Hosaka T, Kobayashi M, Saitoh S, Suzuki Y, Suzuki F. Amino Acid Substitutions in the Hepatitis C Virus Core Region Predict Hepatocarcinogenesis Following Eradication of HCV RNA by All‐Oral Direct‐Acting Antiviral Regimens. J Med Virol. 2018;90(6):1087-93. https://doi.org/10.1002/jmv.25047

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Published

2023-10-26

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Kokanov NS, Jovanović-Ćupić SP, Šiljić MM, Ćirković VS, Petrović NM, Kožik BR, Krajnović MM. Variability of the HCV core region and host genetic and epigenetic factors can predict the response to pegylated interferon/ribavirin therapy in genotype 1b hepatitis C patients from Serbia. Arch Biol Sci [Internet]. 2023Oct.26 [cited 2024Oct.9];75(3):251-62. Available from: https://www.serbiosoc.org.rs/arch/index.php/abs/article/view/8542

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