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Volume 34 Issue 4
August 2019
    Citation: Chunchen Wu, Baolin Li, Xiaoyong Zhang, Kaitao Zhao, Yingshan Chen, Yifei Yuan, Yan Liu, Rongjuan Chen, Dongping Xu, Xinwen Chen, Mengji Lu. Complementation of Wild-Type and Drug-Resistant Hepatitis B Virus Genomes to Maintain Viral Replication and Rescue Virion Production under Nucleos(t)ide Analogs .VIROLOGICA SINICA, 2019, 34(4) : 377-385.  http://dx.doi.org/10.1007/s12250-019-00143-y
    shu

    Complementation of Wild-Type and Drug-Resistant Hepatitis B Virus Genomes to Maintain Viral Replication and Rescue Virion Production under Nucleos(t)ide Analogs

    cstr: 32224.14.s12250-019-00143-y
    • 1.

      Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430070, China

    • 2.

      State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China

    • 3.

      Institute of Virology, University Hospital of Essen, 45122 Essen, Germany

    • 4.

      University of Chinese Academy of Sciences, Beijing 100049, China

    • 5.

      Institute of Infectious Diseases and Liver Failure Research Center, Beijing 302 Hospital, Beijing 100039, China

    • Corresponding author: Xinwen Chen, chenxw@wh.iov.cn, ORCID: 0000-0002-4052-8155
      Mengji Lu, mengji.lu@uni-due.de, ORCID: 0000-0003-4287-9941
    • Received Date: 19 November 2018
      Accepted Date: 14 May 2019
      Published Date: 19 June 2019
      Available online: 01 August 2019
    • As the open reading frames of hepatitis B virus (HBV) genomes are overlapping, resistance mutations (MTs) in HBV polymerase may result in stop codon MTs in hepatitis B surface proteins, which are usually detected as a mixed population with wild-type (WT) HBV. The question was raised how the coexistence of nucleos(t)ide analogs (NAs) resistance MTs and WT sequences affects HBV replication. In the present study, HBV genomes with frequently detected reverse transcriptase (RT)/surface truncation MTs, rtA181T/sW172*, rtV191I/sW182* and rtM204I/sW196*, were phenotypically characterized alone or together with their WT counterparts in different ratios by transient transfection in the absence or presence of NAs. In the absence of NAs, RT/surface truncation MTs impaired the expression and secretion of HBV surface proteins, and had a dose-dependent negative effect on WT HBV virion secretion. However, in the presence of NAs, coexistence of MTs with WT maintained viral replication, and the presence of WT was able to rescue the production of MT HBV virions. Our findings reveal that complementation of WT and MT HBV genomes is highly effective under drug treatment.
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      1. Ahn SH, Park YK, Park ES, Kim JH, Kim DH, Lim KH, Jang MS, Choe WH, Ko SY, Sung IK, Kwon SY, Kim KH (2014) The impact of the hepatitis B virus polymerase rtA181T mutation on replication and drug resistance is potentially affected by overlapping changes in surface gene. J Virol 88:6805-6818
          doi: 10.1128/JVI.00635-14

      2. Cao L, Wu C, Shi H, Gong Z, Zhang E, Wang H, Zhao K, Liu S, Li S, Gao X, Wang Y, Pei R, Lu M, Chen X (2014) Coexistence of hepatitis B virus quasispecies enhances viral replication and the ability to induce host antibody and cellular immune responses. J Virol 88:8656-8666
          doi: 10.1128/JVI.01123-14

      3. Colledge D, Soppe S, Yuen L, Selleck L, Walsh R, Locarnini S, Warner N (2017) Stop codons in the hepatitis B surface proteins are enriched during antiviral therapy and are associated with host cell apoptosis. Virology 501:70-78
          doi: 10.1016/j.virol.2016.11.007

      4. Lai MW, Yeh CT (2008) The oncogenic potential of hepatitis B virus rtA181T/surface truncation mutant. Antivir Ther 13:875-879

      5. Lai MW, Huang SF, Hsu CW, Chang MH, Liaw YF, Yeh CT (2009) Identification of nonsense mutations in hepatitis B virus S gene in patients with hepatocellular carcinoma developed after lamivudine therapy. Antivir Ther 14:249-261

      6. Lambert C, Doring T, Prange R (2007) Hepatitis B virus maturation is sensitive to functional inhibition of ESCRT-Ⅲ, Vps4, and gamma 2-adaptin. J Virol 81:9050-9060
          doi: 10.1128/JVI.00479-07

      7. Lee SA, Kim K, Kim H, Kim BJ (2012) Nucleotide change of codon 182 in the surface gene of hepatitis B virus genotype C leading to truncated surface protein is associated with progression of liver diseases. J Hepatol 56:63-69
          doi: 10.1016/j.jhep.2011.06.028

      8. Li S, Zhao K, Liu S, Wu C, Yao Y, Cao L, Hu X, Zhou Y, Wang Y, Pei R, Lu M, Chen X (2015) HBsAg sT123 N mutation induces stronger antibody responses to HBsAg and HBcAg and accelerates in vivo HBsAg clearance. Virus Res 210:119-125
          doi: 10.1016/j.virusres.2015.08.004

      9. Liu Y, Wang C, Zhong Y, Li X, Dai J, Ren X, Xu Z, Li L, Yao Z, Ji D, Wang L, Zhang L, Wong VW, Zoulim F, Xu D (2011) Genotypic resistance profile of hepatitis B virus (HBV) in a large cohort of nucleos(t)ide analogue-experienced Chinese patients with chronic HBV infection. J Viral Hepat 18:e29-e39
          doi: 10.1111/j.1365-2893.2010.01360.x

      10. Liu Y, Xu Z, Wang Y, Li X, Liu L, Chen L, Xin S, Xu D (2014) rtM204Q may serve as a novel lamivudine-resistance-associated mutation of hepatitis B virus. PLoS ONE 9:e89015
          doi: 10.1371/journal.pone.0089015

      11. Lok AS, McMahon BJ, Brown RS Jr, Wong JB, Ahmed AT, Farah W, Almasri J, Alahdab F, Benkhadra K, Mouchli MA, Singh S, Mohamed EA, Abu Dabrh AM, Prokop LJ, Wang Z, Murad MH, Mohammed K (2016) Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis. Hepatology 63:284-306
          doi: 10.1002/hep.28280

      12. Meng Z, Xu Y, Wu J, Tian Y, Kemper T, Bleekmann B, Roggendorf M, Yang D, Lu M (2008) Inhibition of hepatitis B virus gene expression and replication by endoribonuclease-prepared siRNA. J Virol Methods 150:27-33
          doi: 10.1016/j.jviromet.2008.02.008

      13. Patient R, Hourioux C, Sizaret PY, Trassard S, Sureau C, Roingeard P (2007) Hepatitis B virus subviral envelope particle morphogenesis and intracellular trafficking. J Virol 81:3842-3851
          doi: 10.1128/JVI.02741-06

      14. Patient R, Hourioux C, Roingeard P (2009) Morphogenesis of hepatitis B virus and its subviral envelope particles. Cell Microbiol 11:1561-1570
          doi: 10.1111/cmi.2009.11.issue-11

      15. Pollicino T, Cacciola I, Saffioti F, Raimondo G (2014) Hepatitis B virus PreS/S gene variants: pathobiology and clinical implications. J Hepatol 61:408-417
          doi: 10.1016/j.jhep.2014.04.041

      16. Qin B, Budeus B, Cao L, Wu C, Wang Y, Zhang X, Rayner S, Hoffmann D, Lu M, Chen X (2013) The amino acid substitutions rtP177G and rtF249A in the reverse transcriptase domain of hepatitis B virus polymerase reduce the susceptibility to tenofovir. Antiviral Res 97:93-100
          doi: 10.1016/j.antiviral.2012.12.007

      17. Warner N, Locarnini S (2008) The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound. Hepatology 48:88-98
          doi: 10.1002/hep.v48:1

      18. Wu C, Zhang X, Tian Y, Song J, Yang D, Roggendorf M, Lu M, Chen X (2010) Biological significance of amino acid substitutions in hepatitis B surface antigen (HBsAg) for glycosylation, secretion, antigenicity and immunogenicity of HBsAg and hepatitis B virus replication. J Gen Virol 91:483-492
          doi: 10.1099/vir.0.012740-0

      19. Wu C, Deng W, Deng L, Cao L, Qin B, Li S, Wang Y, Pei R, Yang D, Lu M, Chen X (2012) Amino acid substitutions at positions 122 and 145 of hepatitis B virus surface antigen (HBsAg) determine the antigenicity and immunogenicity of HBsAg and influence in vivo HBsAg clearance. J Virol 86:4658-4669
          doi: 10.1128/JVI.06353-11

      20. Xu S, Pei R, Guo M, Han Q, Lai J, Wang Y, Wu C, Zhou Y, Lu M, Chen X (2012) Cytosolic phospholipase A2 gamma is involved in hepatitis C virus replication and assembly. J Virol 86:13025-13037
          doi: 10.1128/JVI.01785-12

      21. Yao Y, Yang B, Cao H, Zhao K, Yuan Y, Chen Y, Zhang Z, Wang Y, Pei R, Chen J, Hu X, Zhou Y, Lu M, Wu C, Chen X (2018) RBM24 stabilizes hepatitis B virus pregenomic RNA but inhibits core protein translation by targeting the terminal redundancy sequence. Emerg Microbes Infect 7:86

      22. Yeh CT (2010) Development of HBV S gene mutants in chronic hepatitis B patients receiving nucleotide/nucleoside analogue therapy. Antivir Ther 15:471-475
          doi: 10.3851/IMP1552

      23. Yeh CT, Chen T, Hsu CW, Chen YC, Lai MW, Liang KH, Chen TC (2011) Emergence of the rtA181T/sW172* mutant increased the risk of hepatoma occurrence in patients with lamivudine-resistant chronic hepatitis B. BMC Cancer 11:398
          doi: 10.1186/1471-2407-11-398

      24. Zhang X, Zhang E, Ma Z, Pei R, Jiang M, Schlaak JF, Roggendorf M, Lu M (2011) Modulation of hepatitis B virus replication and hepatocyte differentiation by MicroRNA-1. Hepatology 53:1476-1485
          doi: 10.1002/hep.24195

      25. Zhao K, Wu C, Yao Y, Cao L, Zhang Z, Yuan Y, Wang Y, Pei R, Chen J, Hu X, Zhou Y, Lu M, Chen X (2017) Ceruloplasmin inhibits the production of extracellular hepatitis B virions by targeting its middle surface protein. J Gen Virol 98:1410-1421
          doi: 10.1099/jgv.0.000794

      26. Zhao L, Li X, Cheng Y, Chen R, Shao J, Zhou Y, Li Q, Liao H, Zhao Y, Liu L, Su H, Liu Y, Liu Y, Xu D (2018) Hepatitis B virus rtA181T/sW172non-stop mutation may increase resistance fold to adefovir- and entecavir-resistant mutants compared to rtA181T/sW172* mutation. Antiviral Res 154:26-34
          doi: 10.1016/j.antiviral.2018.04.003

      27. Zoulim F, Locarnini S (2009) Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology 137(1593-1608):e1591-e1592
          doi: 10.1053/j.gastro.2009.08.063

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      Complementation of Wild-Type and Drug-Resistant Hepatitis B Virus Genomes to Maintain Viral Replication and Rescue Virion Production under Nucleos(t)ide Analogs

        Corresponding author: Xinwen Chen, chenxw@wh.iov.cn
        Corresponding author: Mengji Lu, mengji.lu@uni-due.de
      • 1. Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430070, China
      • 2. State Key Lab of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
      • 3. Institute of Virology, University Hospital of Essen, 45122 Essen, Germany
      • 4. University of Chinese Academy of Sciences, Beijing 100049, China
      • 5. Institute of Infectious Diseases and Liver Failure Research Center, Beijing 302 Hospital, Beijing 100039, China
      • Received Date: 19 November 2018
      • Accepted Date: 14 May 2019
      • Published Date: 19 June 2019

      Abstract: As the open reading frames of hepatitis B virus (HBV) genomes are overlapping, resistance mutations (MTs) in HBV polymerase may result in stop codon MTs in hepatitis B surface proteins, which are usually detected as a mixed population with wild-type (WT) HBV. The question was raised how the coexistence of nucleos(t)ide analogs (NAs) resistance MTs and WT sequences affects HBV replication. In the present study, HBV genomes with frequently detected reverse transcriptase (RT)/surface truncation MTs, rtA181T/sW172*, rtV191I/sW182* and rtM204I/sW196*, were phenotypically characterized alone or together with their WT counterparts in different ratios by transient transfection in the absence or presence of NAs. In the absence of NAs, RT/surface truncation MTs impaired the expression and secretion of HBV surface proteins, and had a dose-dependent negative effect on WT HBV virion secretion. However, in the presence of NAs, coexistence of MTs with WT maintained viral replication, and the presence of WT was able to rescue the production of MT HBV virions. Our findings reveal that complementation of WT and MT HBV genomes is highly effective under drug treatment.

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