Archives of Virology

, Volume 158, Issue 1, pp 165–172 | Cite as

Hepatitis E virus genotype 4 isolated from a patient with liver failure: full-length sequence analysis showing potential determinants of virus pathogenesis

  • Qiuning Bu
  • Xiaojuan Wang
  • Ling Wang
  • Peng Liu
  • Jiabao Geng
  • Maorong Wang
  • Jian Han
  • Yonghong Zhu
  • Hui Zhuang
Original Article


The full-length genome sequence of a genotype 4 strain of Hepatitis E virus (HEV) (CHN-NJ-H2011) from a patient (in Nanjing, China) with liver failure has been determined. Phylogenetic analysis showed that CHN-NJ-H2011 belongs to genotype 4, subtype 4h. Comparative sequence analysis carried out on a 301-bp fragment of ORF2 showed that CHN-NJ-H2011 shares high nucleotide sequence identity (94.3–94.7 %) with porcine viruses (ch-shsw1 and Ch-estw2) isolated in the same geographical region, pointing to the strong possibility of zoonotic transmission of HEV genotype 4. A broader comparison with other genotype 4 isolates revealed 12 unique amino acid substitutions in ORF1 and three in ORF2 that might serve as signatures of disease severity for genotype 4 HEV infection.


  1. 1.
    Tesse S, Lioure B, Fornecker L, Wendling MJ, Stoll-Keller F, Bigaillon C, Nicand E (2012) Circulation of genotype 4 hepatitis E virus in Europe: first autochthonous hepatitis E infection in France. J Clin Virol 54:197–200PubMedCrossRefGoogle Scholar
  2. 2.
    Aggarwal R (2011) Hepatitis E: historical, contemporary and future perspectives. J Gastroenterol Hepatol 26(Suppl 1):72–82PubMedCrossRefGoogle Scholar
  3. 3.
    Emerson SU, Purcell RH (2003) Hepatitis E virus. Rev Med Virol 13:145–154PubMedCrossRefGoogle Scholar
  4. 4.
    Tei S, Kitajima N, Takahashi K, Mishiro S (2003) Zoonotic transmission of hepatitis E virus from deer to human beings. Lancet 362:371–373PubMedCrossRefGoogle Scholar
  5. 5.
    Miyashita K, Kang JH, Saga A, Takahashi K, Shimamura T, Yasumoto A, Fukushima H, Sogabe S, Konishi K, Uchida T, Fujinaga A, Matsui T, Sakurai Y, Tsuji K, Maguchi H, Taniguchi M, Abe N, Fazle Akbar SM, Arai M, Mishiro S (2012) Three cases of acute or fulminant hepatitis E caused by ingestion of pork meat and entrails in Hokkaido, Japan: zoonotic food-borne transmission of hepatitis E virus and public health concerns. Hepatol Res. doi:10.1111/j.1872-034X.2012.01006.x
  6. 6.
    Tamada Y, Yano K, Yatsuhashi H, Inoue O, Mawatari F, Ishibashi H (2004) Consumption of wild boar linked to cases of hepatitis E. J Hepatol 40:869–870PubMedCrossRefGoogle Scholar
  7. 7.
    Khuroo MS, Kamili S, Yattoo GN (2004) Hepatitis E virus infection may be transmitted through blood transfusions in an endemic area. J Gastroenterol Hepatol 19:778–784PubMedCrossRefGoogle Scholar
  8. 8.
    Khuroo MS, Kamili S, Khuroo MS (2009) Clinical course and duration of viremia in vertically transmitted hepatitis E virus (HEV) infection in babies born to HEV-infected mothers. J Viral Hepat 16:519–523PubMedCrossRefGoogle Scholar
  9. 9.
    Purcell RH, Emerson SU (2008) Hepatitis E: an emerging awareness of an old disease. J Hepatol 48:494–503PubMedCrossRefGoogle Scholar
  10. 10.
    Ahmad I, Holla RP, Jameel S (2011) Molecular virology of hepatitis E virus. Virus Res 161:47–58PubMedCrossRefGoogle Scholar
  11. 11.
    Kamar N, Selves J, Mansuy JM, Ouezzani L, Peron JM, Guitard J, Cointault O, Esposito L, Abravanel F, Danjoux M, Durand D, Vinel JP, Izopet J, Rostaing L (2008) Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med 358:811–817PubMedCrossRefGoogle Scholar
  12. 12.
    Haagsma EB, van den Berg AP, Porte RJ, Benne CA, Vennema H, Reimerink JH, Koopmans MP (2008) Chronic hepatitis E virus infection in liver transplant recipients. Liver Transpl 14:547–553PubMedCrossRefGoogle Scholar
  13. 13.
    Dalton HR, Bendall RP, Keane FE, Tedder RS, Ijaz S (2009) Persistent carriage of hepatitis E virus in patients with HIV infection. N Engl J Med 361:1025–1027PubMedCrossRefGoogle Scholar
  14. 14.
    Ollier L, Tieulie N, Sanderson F, Heudier P, Giordanengo V, Fuzibet JG, Nicand E (2009) Chronic hepatitis after hepatitis E virus infection in a patient with non-Hodgkin lymphoma taking rituximab. Ann Intern Med 150:430–431PubMedGoogle Scholar
  15. 15.
    Ramachandran J, Eapen CE, Kang G, Abraham P, Hubert DD, Kurian G, Hephzibah J, Mukhopadhya A, Chandy GM (2004) Hepatitis E superinfection produces severe decompensation in patients with chronic liver disease. J Gastroenterol Hepatol 19:134–138PubMedCrossRefGoogle Scholar
  16. 16.
    Hamid SS, Atiq M, Shehzad F, Yasmeen A, Nissa T, Salam A, Siddiqui A, Jafri W (2002) Hepatitis E virus superinfection in patients with chronic liver disease. Hepatology 36:474–478PubMedCrossRefGoogle Scholar
  17. 17.
    Acharya SK, Sharma PK, Singh R, Mohanty SK, Madan K, Jha JK, Panda SK (2007) Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death. J Hepatol 46:387–394CrossRefGoogle Scholar
  18. 18.
    Monga R, Garg S, Tyagi P, Kumar N (2004) Superimposed acute hepatitis E infection in patients with chronic liver disease. Indian J Gastroenterol 23:50–52PubMedGoogle Scholar
  19. 19.
    Lu FM, Zhuang H (2009) Management of hepatitis B in China. Chin Med J 122:3–4PubMedGoogle Scholar
  20. 20.
    Shang QH, Yu JG, Xiao DM, Xu CZ, Chen CX, Zhang GS (2002) The effects of hepatitis E virus superinfection on patients with chronic hepatitis B: a clinic-pathological study. Zhonghua Nei Ke Zazhi 41:656–659Google Scholar
  21. 21.
    Meng XJ (2010) Hepatitis E virus: animal reservoirs and zoonotic risk. Vet Microbiol 140:256–265PubMedCrossRefGoogle Scholar
  22. 22.
    Meng XJ, Purcell RH, Halbur PG, Lehman JR, Webb DM, Tsareva TS, Haynes JS, Thacker BJ, Emerson SU (1997) A novel virus in swine is closely related to the human hepatitis E virus. Proc Natl Acad Sci USA 94:9860–9865PubMedCrossRefGoogle Scholar
  23. 23.
    Zheng Y, Ge S, Zhang J, Guo Q, Ng MH, Wang F, Xia N, Jiang Q (2006) Swine as a principal reservoir of hepatitis E virus that infects humans in eastern China. J Infect Dis 193:1643–1649PubMedCrossRefGoogle Scholar
  24. 24.
    Ning H, Niu Z, Yu R, Zhang P, Dong S, Li Z (2007) Identification of genotype 3 hepatitis E virus in fecal samples from a pig farm located in a Shanghai suburb. Vet Microbiol 121:125–130PubMedCrossRefGoogle Scholar
  25. 25.
    Wang YC (2003) Epidemiology, molecular biology and zoonosis of genotype IV hepatitis E in China. Chin J Epidemiol 24:618–622Google Scholar
  26. 26.
    Geng JB, Wang MR, Wang L, Wang J, Yang ZG, Cheng Y, Qiao F, Wang M (2012) Genetic characteristics and pathogenicity of human hepatitis E virus in Nanjing, China. World J Gastroenterol 18:965–970PubMedCrossRefGoogle Scholar
  27. 27.
    Fu H, Wang L, Zhu Y, Geng J, Li L, Wang X, Bu Q, Zhuang H (2011) Analysing complete genome sequence of swine hepatitis E virus (HEV), strain CHN-XJ-SW13 isolated from Xinjiang, China: putative host range, and disease severity determinants in HEV. Infect Genet Evol 11:618–623PubMedCrossRefGoogle Scholar
  28. 28.
    Graff J, Torian U, Nguyen H, Emerson SU (2006) A bicistronic subgenomic mRNA encodes both the ORF2 and ORF3 proteins of hepatitis E virus. J Virol 80:5919–5926PubMedCrossRefGoogle Scholar
  29. 29.
    Huang YW, Opriessnig T, Halbur PG, Meng XJ (2007) Initiation at the third in-frame AUG codon of open reading frame 3 of the hepatitis E virus is essential for viral infectivity in vivo. J Virol 81:3018–3026PubMedCrossRefGoogle Scholar
  30. 30.
    Zhu YM, Dong SJ, Si FS, Yu RS, Li Z, Yu XM (2011) Swine and human hepatitis E virus (HEV) infection in China. J Clin Virol 52:155–157PubMedCrossRefGoogle Scholar
  31. 31.
    Huang FF, Sun ZF, Emerson SU, Purcell RH, Shivaprasad HL, Pierson FW, Toth TE, Meng XJ (2004) Determination and analysis of the complete genomic sequence of avian hepatitis E virus (avian HEV) and attempts to infect rhesus monkeys with avian HEV. J Gen Virol 85:1609–1618PubMedCrossRefGoogle Scholar
  32. 32.
    Wang Y, Zhang H, Ling R, Li H, Harrison TJ (2000) The complete sequence of hepatitis E virus genotype 4 reveals an alternative strategy for translation of open reading frames 2 and 3. J Gen Virol 81:1675–1686PubMedGoogle Scholar
  33. 33.
    Geng JB, Wang L, Wang XJ, Fu HW, Bu QN, Liu P, Zhu YH, Wang MR, Sui YH, Zhuang H (2011) Potential risk of zoonotic transmission from young swine to human: seroepidemiological and genetic characterization of hepatitis E virus in human and various animals in Beijing, China. J Viral Hepat 18:e583–e590PubMedCrossRefGoogle Scholar
  34. 34.
    Zhu YM, Si FS, Cao DJ, XM Y, Yu RS, Dong SJ, Huang FF, Li Z (2011) Molecular epidemiology of hepatitis E virus infections in Shanghai, China. J Virol 8:541CrossRefGoogle Scholar
  35. 35.
    Inoue J, Nishizawa T, Takahashi M, Aikawa T, Mizuo H, Suzuki K, Shimosegawa T, Okamoto H (2006) Analysis of the full-length genome of genotype 4 hepatitis E virus isolates from patients with fulminant or acute self-limited hepatitis E. J Med Virol 78:476–484PubMedCrossRefGoogle Scholar
  36. 36.
    Inoue J, Takahashi M, Mizuo H, Suzuki K, Aikawa T, Shimosegawa T, Okamoto H (2009) Nucleotide substitutions of hepatitis E virus genomes associated with fulminant hepatitis and disease severity. Tohoku J Exp Med 218:279–284PubMedCrossRefGoogle Scholar
  37. 37.
    Aggarwal R, Naik S (2009) Epidemiology of hepatitis E: current status. J Gastroenterol Hepatol 24:1484–1493PubMedCrossRefGoogle Scholar
  38. 38.
    Acharya SK, Panda SK (2006) Hepatitis E virus: epidemiology, diagnosis, pathology and prevention. Trop Gastroenterol 27:63–68PubMedGoogle Scholar
  39. 39.
    Dalton HR, Hazeldine S, Banks M, Ijaz S, Bendall R (2007) Locally acquired hepatitis E in chronic liver disease. Lancet 369:1260PubMedCrossRefGoogle Scholar
  40. 40.
    Peron JM, Bureau C, Poirson H, Mansuy JM, Alric L, Selves J, Dupuis E, Izopet J, Vinel JP (2007) Fulminant liver failure from acute autochthonous hepatitis E in France: description of seven patients with acute hepatitis E and encephalopathy. J Viral Hepat 14:298–303PubMedCrossRefGoogle Scholar
  41. 41.
    Zhu FC, Zhang J, Zhang XF, Zhou C, Wang ZZ, Huang SJ, Wang H, Yang CL, Jiang HM, Cai JP, Wang YJ, Ai X, Hu YM, Tang Q, Yao X, Yan Q, Xian YL, Wu T, Li YM, Miao J, Ng MH, Shih JW, Xia NS (2010) Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet 376:895–902PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2012

Authors and Affiliations

  • Qiuning Bu
    • 1
    • 3
  • Xiaojuan Wang
    • 1
  • Ling Wang
    • 1
  • Peng Liu
    • 1
  • Jiabao Geng
    • 2
  • Maorong Wang
    • 2
  • Jian Han
    • 1
  • Yonghong Zhu
    • 1
  • Hui Zhuang
    • 1
  1. 1.Department of Microbiology, School of Basic Medical Sciences, Peking University Infectious Disease CenterPeking UniversityBeijingChina
  2. 2.Institute of HepatologyThe 81st Hospital of PLANanjingChina
  3. 3.Clinical LaboratoryThe First Hospital of QinhuangdaoQinhuangdaoChina

Personalised recommendations