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Quasispecies characters of hepatitis B virus in immunoprophylaxis failure infants

  • Xin Wang
  • Wanyan Deng
  • Keli Qian
  • Haijun Deng
  • Yong Huang
  • Zeng Tu
  • Ailong Huang
  • Quanxin Long
Original Article
  • 188 Downloads

Abstract

Hepatitis B vaccination prevents 80–95% of transmission and reduces the incidence of HBV in children. The variations in the a determinant of HBV surface antigen (HBsAg) have been reported to be the most prevalent cause for vaccine or antibody escape. There is a conflicting evidence on as to whether escape mutants arise de novo in infected infants or whether the mutants, that have preexisted maternally, subsequently undergo selective replication in the infant under immune pressure. Here, we report that nearly 65% (55 of 85) vaccination failure in child patients has no amino acid substitution in a determinant as seen by Sanger sequencing. We further employed an Illumina sequencing platform-based method to detect HBV quasispecies in four immunoprophylaxis failure infants and their mothers. In our data, the substitution rate of amino acid located at a determinant is relatively low (< 10%), I/T126A, C124S, F134Y, K141Q, Q129H, D144A, G145V, and N146K, which showed no statistical difference to their mothers, proving that these vaccine escape mutants preexist maternally as minor variants. Besides that, bioinformatical analysis showed that the binding affinity of high variation epitopes (amino acid divergence in mother and their infants > 20%) to related HLA molecules was generally decreased, these traces of immune escape suggesting that immune pressure was present and was effective in all samples.

Keywords

Hepatitis B virus Ultra-deep sequencing Immunoprophylaxis failure infants a determinant substitution 

Notes

Funding

This work was supported by the National Science and Technology Major Project (2017ZX10202203), Research Plan from Nanan Health and Family Planning Commission (2017-38) and the National Natural Science Foundation of China (81501751).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Enrollment in the clinical study as well as the usage of patient serum samples for HBV sequencing studies were approved by the Chongqing Medical University ethics committee.

Informed consent

Written informed consent for participation in this study was obtained from all adult patients or caretakers on behalf of the children enrolled in this study.

Supplementary material

10096_2018_3235_MOESM1_ESM.docx (409 kb)
ESM 1 (DOCX 408 kb)

References

  1. 1.
    Dienstag JL (2008) Hepatitis B virus infection. N Engl J Med 359(14):1486–1500CrossRefPubMedGoogle Scholar
  2. 2.
    Peveling-Oberhag J, Herrmann E, Kronenberger B, Farnik H, Susser S, Sarrazin C, Zeuzem S, Hofmann WP (2013) Dynamics of hepatitis B virus quasispecies heterogeneity and virologic response in patients receiving low-to-moderate genetic barrier nucleoside analogs. J Viral Hepat 20(4):234–239CrossRefPubMedGoogle Scholar
  3. 3.
    Rodriguez C, Chevaliez S, Bensadoun P, Pawlotsky JM (2013) Characterization of the dynamics of hepatitis B virus resistance to adefovir by ultra-deep pyrosequencing. HepatologyGoogle Scholar
  4. 4.
    Shao ZJ, Zhang L, Xu JQ, Xu DZ, Men K, Zhang JX, Cui HC, Yan YP (2011) Mother-to-infant transmission of hepatitis B virus: a Chinese experience. J Med Virol 83(5):791–795CrossRefPubMedGoogle Scholar
  5. 5.
    Chen DS (2009) Hepatitis B vaccination: the key towards elimination and eradication of hepatitis B. J Hepatol 50(4):805–816CrossRefPubMedGoogle Scholar
  6. 6.
    Hsu HY, Chang MH, Liaw SH, Ni YH, Chen HL (1999) Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in Taiwan. Hepatology 30(5):1312–1317CrossRefPubMedGoogle Scholar
  7. 7.
    Ni YH (2011) Natural history of hepatitis B virus infection: pediatric perspective. J Gastroenterol 46(1):1–8CrossRefPubMedGoogle Scholar
  8. 8.
    Yamamoto K, Horikita M, Tsuda F, Itoh K, Akahane Y, Yotsumoto S, Okamoto H, Miyakawa Y, Mayumi M (1994) Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen. J Virol 68(4):2671–2676PubMedPubMedCentralGoogle Scholar
  9. 9.
    Carman WF, Korula J, Wallace L, MacPhee R, Mimms L, Decker R (1995) Fulminant reactivation of hepatitis B due to envelope protein mutant that escaped detection by monoclonal HBsAg ELISA. Lancet 345(8962):1406–1407CrossRefPubMedGoogle Scholar
  10. 10.
    Bian T, Yan H, Shen L, Wang F, Zhang S, Cao Y, Zhang Y, Bi S (2013) Change in hepatitis B virus large surface antigen variant prevalence 13 years after implementation of a universal vaccination program in China. J Virol 87(22):12196–12206CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Hsu HY, Chang MH, Ni YH, Chen HL (2004) Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan. Gut 53(10):1499–1503CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Desmond CP, Bartholomeusz A, Gaudieri S, Revill PA, Lewin SR (2008) A systematic review of T-cell epitopes in hepatitis B virus: identification, genotypic variation and relevance to antiviral therapeutics. Antivir Ther 13(2):161–175PubMedGoogle Scholar
  13. 13.
    Parker KC, Bednarek MA, Coligan JE (1994) Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol 152(1):163–175PubMedGoogle Scholar
  14. 14.
    Liu F, Yu DM, Huang SY, Yu JL, Zhang DH, Gong QM, Zhang XX (2014) Clinical implications of evolutionary patterns of homologous, full-length hepatitis B virus quasispecies in different hosts after perinatal infection. J Clin Microbiol 52(5):1556–1565CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Wang C, Mitsuya Y, Gharizadeh B, Ronaghi M, Shafer RW (2007) Characterization of mutation spectra with ultra-deep pyrosequencing: application to HIV-1 drug resistance. Genome Res 17(8):1195–1201CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kagan RM, Johnson EP, Siaw M, Biswas P, Chapman DS, Su Z, Platt JL, Pesano RL (2012) A genotypic test for HIV-1 tropism combining Sanger sequencing with ultradeep sequencing predicts virologic response in treatment-experienced patients. PLoS One 7(9):e46334CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Dietz J, Schelhorn SE, Fitting D, Mihm U, Susser S, Welker MW, Fuller C, Daumer M, Teuber G, Wedemeyer H et al (2013) Deep sequencing reveals mutagenic effects of ribavirin during monotherapy of hepatitis C virus genotype 1-infected patients. J Virol 87(11):6172–6181CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Torresi J (2002) The virological and clinical significance of mutations in the overlapping envelope and polymerase genes of hepatitis B virus. J Clin Virol 25(2):97–106CrossRefPubMedGoogle Scholar
  19. 19.
    Ghany MG, Ayola B, Villamil FG, Gish RG, Rojter S, Vierling JM, Lok AS (1998) Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis. Hepatology 27(1):213–222CrossRefPubMedGoogle Scholar
  20. 20.
    Wood N, Bhattacharya T, Keele BF, Giorgi E, Liu M, Gaschen B, Daniels M, Ferrari G, Haynes BF, McMichael A et al (2009) HIV evolution in early infection: selection pressures, patterns of insertion and deletion, and the impact of APOBEC. PLoS Pathog 5(5):e1000414CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Zhang L, Gui XE, Teter C, Zhong H, Pang Z, Ding L, Li F, Zhou Y (2014) Effects of hepatitis B immunization on prevention of mother-to-infant transmission of hepatitis B virus and on the immune response of infants towards hepatitis B vaccine. Vaccine 32(46):6091–6097CrossRefPubMedGoogle Scholar
  22. 22.
    Duan Z, Chen X, Liang Z, Zeng Y, Zhu F, Long L, McCrae MA, Zhuang H, Shen T, Lu F (2014) Genetic polymorphisms of CXCR5 and CXCL13 are associated with non-responsiveness to the hepatitis B vaccine. Vaccine 32(41):5316–5322CrossRefPubMedGoogle Scholar
  23. 23.
    Hsu HY, Chang MH, Ni YH, Chiang CL, Wu JF, Chen HL (2015) Universal infant immunization and occult hepatitis B virus infection in children and adolescents: a population-based study. Hepatology 61(4):1183–1191CrossRefPubMedGoogle Scholar
  24. 24.
    Carman WF (1997) The clinical significance of surface antigen variants of hepatitis B virus. J Viral Hepat 4(Suppl 1):11–20CrossRefPubMedGoogle Scholar
  25. 25.
    Ngui SL, O'Connell S, Eglin RP, Heptonstall J, Teo CG (1997) Low detection rate and maternal provenance of hepatitis B virus S gene mutants in cases of failed postnatal immunoprophylaxis in England and Wales. J Infect Dis 176(5):1360–1365CrossRefPubMedGoogle Scholar
  26. 26.
    Nainan OV, Khristova ML, Byun K, Xia G, Taylor PE, Stevens CE, Margolis HS (2002) Genetic variation of hepatitis B surface antigen coding region among infants with chronic hepatitis B virus infection. J Med Virol 68(3):319–327CrossRefPubMedGoogle Scholar
  27. 27.
    Fuller CW, Middendorf LR, Benner SA, Church GM, Harris T, Huang X, Jovanovich SB, Nelson JR, Schloss JA, Schwartz DC et al (2009) The challenges of sequencing by synthesis. Nat Biotechnol 27(11):1013–1023CrossRefPubMedGoogle Scholar
  28. 28.
    Wang YQ, Ren YF, Song YJ, Xue YF, Zhang XJ, Cao ST, Deng ZJ, Wu J, Chen L, Li G et al (2014) MicroRNA-581 promotes hepatitis B virus surface antigen expression by targeting Dicer and EDEM1. Carcinogenesis 35(9):2127–2133CrossRefPubMedGoogle Scholar
  29. 29.
    Kim D, Lyoo KS, Smith D, Hur W, Hong SW, Sung PS, Yoon SK, Mehta S (2011) Number of mutations within CTL-defined epitopes of the hepatitis B virus (HBV) core region is associated with HBV disease progression. J Med Virol 83(12):2082–2087CrossRefPubMedGoogle Scholar
  30. 30.
    Mishra A, Rao KV, Durgapal H, Manivel V, Panda SK (1993) Human T-helper cell responses to a synthetic peptide derived from the hepatitis B surface antigen. Immunology 79(3):362–367PubMedPubMedCentralGoogle Scholar
  31. 31.
    Henn MR, Boutwell CL, Charlebois P, Lennon NJ, Power KA, Macalalad AR, Berlin AM, Malboeuf CM, Ryan EM, Gnerre S et al (2012) Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection. PLoS Pathog 8(3):e1002529CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Mizukoshi E, Sidney J, Livingston B, Ghany M, Hoofnagle JH, Sette A, Rehermann B (2004) Cellular immune responses to the hepatitis B virus polymerase. J Immunol 173(9):5863–5871CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated HospitalChongqing Medical UniversityChongqingPeople’s Republic of China
  2. 2.Collaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesHangzhouPeople’s Republic of China
  3. 3.Department of Infectious DiseaseThe Fifth People’s Hospital of ChongqingChongqingPeople’s Republic of China
  4. 4.Clinical laboratory, The Second Affiliated HospitalChongqing Medical UniversityChongqingPeople’s Republic of China

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