Skip to main content

Advertisement

Log in

Identification of a new hepatitis B virus recombinant D2/D3 in the city of São Paulo, Brazil

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

Two hundred forty million people are chronically infected with hepatitis B virus (HBV) worldwide. The rise of globalization has facilitated the emergence of novel HBV recombinants and genotypes. We evaluated HBV genotypes and recombinants, mutations associated with resistance to antivirals (AVs), progression of hepatic illness, and inefficient hepatitis B vaccination responses in chronically infected individuals in the city of São Paulo, Brazil. Forty-five full-length and 24 partial-length sequences were obtained. The genotype distribution was as follows: A (66.7%), D (15.9%), F (11.6%) and C (4.3%). We describe a new recombinant (D2/D3), confirmed through next-generation sequencing (NGS) and reconstruction of the quasispecies sequences in silico. Primary resistance and major vaccine escape mutations were not found. We did, however, find mutations in the S region that might may be related to HBV antigenicity changes, as well as Pre-S deletions. The precore/core mutations A1762T + G1764A (40.9%) were found mostly in genotypes A and D, and G1896A (29.55%) was more frequent in genotype D than in genotype A. The genotypic distribution reflects the history of Brazilian immigration. This is the first description of recombination between genotypes D2 and D3 in Brazil. It is also the first confirmation through NGS and reconstruction of the quasispecies in silico. However, little is known about the response to treatment of recombinants. This demonstrates the need for molecular epidemiology studies involving the analysis of full-length HBV sequences.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. WHO (2014) Hepatitis B. World Health Organization

  2. Kay A, Zoulim F (2007) Hepatitis B virus genetic variability and evolution. Virus Res 127(2):164–176. doi:10.1016/j.virusres.2007.02.021

    Article  CAS  PubMed  Google Scholar 

  3. McMahon BJ (2009) The influence of hepatitis B virus genotype and subgenotype on the natural history of chronic hepatitis B. Hepatol Int 3(2):334–342. doi:10.1007/s12072-008-9112-z

    Article  PubMed  Google Scholar 

  4. Bottecchia M, Souto FJ, Kycia OM, Amendola M, Brandao CE, Niel C, Gomes SA (2008) Hepatitis B virus genotypes and resistance mutations in patients under long term lamivudine therapy: characterization of genotype G in Brazil. BMC Microbiol 8:11. doi:10.1186/1471-2180-8-11

    Article  PubMed  PubMed Central  Google Scholar 

  5. Mello FC, Souto FJ, Nabuco LC, Villela-Nogueira CA, Coelho HS, Franz HC, Saraiva JC, Virgolino HA, Motta-Castro AR, Melo MM, Martins RM, Gomes SA (2007) Hepatitis B virus genotypes circulating in Brazil: molecular characterization of genotype F isolates. BMC Microbiol 7:103. doi:10.1186/1471-2180-7-103

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sitnik R, Pinho JR, Bertolini DA, Bernardini AP, Da Silva LC, Carrilho FJ (2004) Hepatitis B virus genotypes and precore and core mutants in Brazilian patients. J Clin Microbiol 42(6):2455–2460. doi:10.1128/JCM.42.6.2455-2460.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sitnik R, Sette H Jr, Santana RA, Menezes LC, Graca CH, Dastoli GT, Silbert S, Pinho JR (2007) Hepatitis B virus genotype E detected in Brazil in an African patient who is a frequent traveler. Braz J Med Biol Res 40(12):1689–1692

    Article  CAS  PubMed  Google Scholar 

  8. Liao Y, Hu X, Chen J, Cai B, Tang J, Ying B, Wang H, Wang L (2012) Precore mutation of hepatitis B virus may contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis. PloS One 7(6):e38394. doi:10.1371/journal.pone.0038394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kamili S, Sozzi V, Thompson G, Campbell K, Walker CM, Locarnini S, Krawczynski K (2009) Efficacy of hepatitis B vaccine against antiviral drug-resistant hepatitis B virus mutants in the chimpanzee model. Hepatology 49(5):1483–1491. doi:10.1002/hep.22796

    Article  CAS  PubMed  Google Scholar 

  10. Zhang Q, Wu G, Richards E, Jia S, Zeng C (2007) Universal primers for HBV genome DNA amplification across subtypes: a case study for designing more effective viral primers. Virol J 4:92. doi:10.1186/1743-422X-4-92

    Article  PubMed  PubMed Central  Google Scholar 

  11. De Castro L, Niel C, Gomes SA (2001) Low frequency of mutations in the core promoter and precore regions of hepatitis B virus in anti-HBe positive Brazilian carriers. BMC Microbiol 1:10

    Article  PubMed  PubMed Central  Google Scholar 

  12. Stuyver LJ, Locarnini SA, Lok A, Richman DD, Carman WF, Dienstag JL, Schinazi RF (2001) Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region. Hepatology 33(3):751–757. doi:10.1053/jhep.2001.22166

    Article  CAS  PubMed  Google Scholar 

  13. de Barros JJ, Peres LR, de Sousa PS, do do Amaral Mello FC, de Araujo NM, de Andrade Gomes S, Niel C, Lewis-Ximenez LL (2015) Occult infection with HBV intergenotypic A2/G recombinant following acute hepatitis B caused by an HBV/A2 isolate. J Clin Virol 67:31–35. doi:10.1016/j.jcv.2015.03.019

    Article  PubMed  Google Scholar 

  14. Araujo NM, Araujo OC, Silva EM, Villela-Nogueira CA, Nabuco LC, Parana R, Bessone F, Gomes SA, Trepo C, Kay A (2013) Identification of novel recombinants of hepatitis B virus genotypes F and G in human immunodeficiency virus-positive patients from Argentina and Brazil. J Gen Virol 94(Pt 1):150–158. doi:10.1099/vir.0.047324-0

    Article  CAS  PubMed  Google Scholar 

  15. Araujo NM (2015) Hepatitis B virus intergenotypic recombinants worldwide: an overview. Infect Genet Evol. doi:10.1016/j.meegid.2015.08.024

    PubMed  Google Scholar 

  16. Lago BV, Mello FC, Kramvis A, Niel C, Gomes SA (2014) Hepatitis B virus subgenotype A1: evolutionary relationships between Brazilian, African and Asian isolates. PloS One 9(8):e105317. doi:10.1371/journal.pone.0105317

    Article  PubMed  PubMed Central  Google Scholar 

  17. Schaefer S (2007) Hepatitis B virus genotypes in Europe. Hepatol Res 37(s1):S20–S26. doi:10.1111/j.1872-034X.2007.00099.x

    Article  CAS  PubMed  Google Scholar 

  18. Bertolini DA, Gomes-Gouvea MS, Guedes de Carvalho-Mello IM, Saraceni CP, Sitnik R, Grazziotin FG, Laurino JP, Fagundes NJ, Carrilho FJ, Pinho JR (2012) Hepatitis B virus genotypes from European origin explains the high endemicity found in some areas from southern Brazil. Infect Genet Evol 12(6):1295–1304. doi:10.1016/j.meegid.2012.04.009

    Article  PubMed  Google Scholar 

  19. Gusatti CS, Costi C, Halon ML, Grandi T, Medeiros AFR, Silva CMD, Gomes SA, Silva MSN, Niel C, Rossetti MLR (2015) Hepatitis B virus genotype D Isolates circulating in Chapecó, Southern Brazil, originate from Italy. PloS One 10(8):e0135816

    Article  PubMed  PubMed Central  Google Scholar 

  20. Barros LMF, Gomes-Gouvea MS, Kramvis A, Mendes-Corrêa MCJ, dos Santos A, Souza LAB, Santos MDC, Carrilho FJ, de Jesus Domicini A, Pinho JRR (2014) High prevalence of hepatitis B virus subgenotypes A1 and D4 in Maranhão state, Northeast Brazil. Infect Genet Evol 24:68–75

    Article  PubMed  Google Scholar 

  21. Gomes-Gouvea MS, Soares MC, Bensabath G, de Carvalho-Mello IM, Brito EM, Souza OS, Queiroz AT, Carrilho FJ, Pinho JR (2009) Hepatitis B virus and hepatitis delta virus genotypes in outbreaks of fulminant hepatitis (Labrea black fever) in the western Brazilian Amazon region. J Gen Virol 90(Pt 11):2638–2643. doi:10.1099/vir.0.013615-0

    Article  CAS  PubMed  Google Scholar 

  22. Alvarado-Mora MV, Pinho JR (2013) Distribution of HBV genotypes in Latin America. Antivir Ther 18(3 Pt B):459–465

    Article  PubMed  Google Scholar 

  23. Lin CL, Kao JH (2011) The clinical implications of hepatitis B virus genotype: Recent advances. J Gastroenterol Hepatol 26(Suppl 1):123–130. doi:10.1111/j.1440-1746.2010.06541.x

    Article  PubMed  Google Scholar 

  24. Gomes-Gouvea MS, Ferreira AC, Teixeira R, Andrade JR, Ferreira AS, Barros LM, Rezende RE, Nastri AC, Leite AG, Piccoli LZ, Galvan J, Conde SR, Soares MC, Kliemann DA, Bertolini DA, Kunyoshi AS, Lyra AC, Oikawa MK, de Araujo LV, Carrilho FJ, Mendes-Correa MC, Rebello Pinho JR (2015) HBV carrying drug-resistance mutations in chronically infected treatment-naive patients. Antivir Ther. doi:10.3851/IMP2938

    Google Scholar 

  25. Mantovani N, Cicero M, Santana LC, Silveira C, do Carmo EP, Abrao PR, Diaz RS, Caseiro MM, Komninakis SV (2013) Detection of lamivudine-resistant variants and mutations related to reduced antigenicity of HBsAg in individuals from the cities of Santos and Sao Paulo, Brazil. Virol J 10:320. doi:10.1186/1743-422X-10-320

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wallace L, Carman W (1997) Surface gene variation of HBV: scientific and medical relevance. Viral Hepat Rev 3:5–16

    Google Scholar 

  27. Westhoff TH, Jochimsen F, Schmittel A, Stoffler-Meilicke M, Schafer JH, Zidek W, Gerlich WH, Thiel E (2003) Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy. Blood 102(5):1930. doi:10.1182/blood-2003-05-1403

    Article  CAS  PubMed  Google Scholar 

  28. Mantovani N, Cicero M, Santana LC, Silveira C, do Carmo EP, Abrao PR, Diaz RS, Caseiro MM, Komninakis SV (2013) Detection of lamivudine-resistant variants and mutations related to reduced antigenicity of HBsAg in individuals from the cities of Santos and Sao Paulo, Brazil. Virol J 10(1):320. doi:10.1186/1743-422X-10-320

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bock CT, Kubicka S, Manns MP, Trautwein C (1999) Two control elements in the hepatitis B virus S-promoter are important for full promoter activity mediated by CCAAT-binding factor. Hepatology 29(4):1236–1247. doi:10.1002/hep.510290426

    Article  CAS  PubMed  Google Scholar 

  30. Xu Z, Jensen G, Yen TS (1997) Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum. J Virol 71(10):7387–7392

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Lok AS, Akarca U, Greene S (1994) Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci USA 91(9):4077–4081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chan HL, Hussain M, Lok AS (1999) Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion. Hepatology 29(3):976–984. doi:10.1002/hep.510290352

    Article  CAS  PubMed  Google Scholar 

  33. Juniastuti Utsumi T, Aksono EB, Yano Y, Soetjipto Hayashi Y, Hotta H, Rantam FA, Kusumobroto HO, Lusida MI (2013) Predominance of precore mutations and clinical significance of basal core promoter mutations in chronic hepatitis B virus infection in Indonesia. Biomed Rep 1(4):522–528. doi:10.3892/br.2013.106

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Rezende RE, Fonseca BA, Ramalho LN, Zucoloto S, Pinho JR, Bertolini DA, Martinelli AL (2005) The precore mutation is associated with severity of liver damage in Brazilian patients with chronic hepatitis B. J Clin Virol 32(1):53–59. doi:10.1016/j.jcv.2004.08.001

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the São Paulo Research Foundation and National Council of Technological and Scientific Development for financial support. We would also like to thank all the patients who enabled this study to be conducted.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shirley Vasconcelos Komninakis.

Ethics declarations

Funding

This study was Funded by São Paulo Research Foundation (FAPESP Grant#2012/13285-0) and National Council of Technological and Scientific Development (CNPq Grant# 141858/2013-3).

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Santana, L.C., Mantovani, N.P., Ferreira, M.C. et al. Identification of a new hepatitis B virus recombinant D2/D3 in the city of São Paulo, Brazil. Arch Virol 162, 457–467 (2017). https://doi.org/10.1007/s00705-016-3122-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-016-3122-2

Keywords

Navigation