Hepatology International

, Volume 11, Issue 6, pp 500–508 | Cite as

Hepatitis B virus: virology, molecular biology, life cycle and intrahepatic spread

  • P. KarayiannisEmail author
Review Article


Hepatitis B virus is a member of the Hepadnaviridae family and responsible for causing acute and chronic hepatitis in humans. The current estimates of people chronically infected with the virus are put at 250 million worldwide. Immune-mediated liver damage in these individuals may lead to the development of cirrhosis and hepatocellular carcinoma later in life. This review deals with our current understanding of the virology, molecular biology, life cycle and cell-to-cell spread of this very important pathogen, all of which are considered essential for current and future approaches to antiviral treatment.


Hepatitis B virus Life cycle Replication Molecular virology Genotypes Cell-to-cell spread 


Compliance with ethical standards

Conflict of interest

P. Karayiannis has no conflicts of interest.

Human rights

No research involving human participants and/or animals.


  1. 1.
    WHO factsheet no. 204. Accessed 14 June 2017
  2. 2.
    El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012;142:1264–1273CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2095–2128CrossRefPubMedGoogle Scholar
  4. 4.
    Krugman S, Giles JP, Hammond J. Infectious hepatitis. Evidence for two distinctive clinical, epidemiological, and immunological types of infection. JAMA 1967;200:365–373CrossRefPubMedGoogle Scholar
  5. 5.
    Giles JP, McCollum RW, Berndtson LW Jr, Krugman S. Relation of Australia-SH antigen to the willowbrook MS-2 strain. N Engl J Med 1969;281:119–122CrossRefPubMedGoogle Scholar
  6. 6.
    Blumberg BS, Alter HJ, Visnich S. A “new” antigen in leukemia sera. JAMA 1965;191:541–546CrossRefPubMedGoogle Scholar
  7. 7.
    Bayer ME, Blumberg BS, Werner B. Particles associated with Australia antigen in the sera of patients with leukaemia. Down’s Syndrome and hepatitis. Nature 1968;218:1057–1059PubMedGoogle Scholar
  8. 8.
    Prince AM. Detection of serum hepatitis virus carriers by testing for the SH (Australia) antigen. A review of current methodology. Vox Sang 1970;19:417–424CrossRefPubMedGoogle Scholar
  9. 9.
    Dane DS, Cameron CH, Briggs M. Virus-like particles in serum of patients with Australia-antigen-associated hepatitis. Lancet 1970;1:695–698CrossRefPubMedGoogle Scholar
  10. 10.
    Robinson WS. DNA and DNA polymerase in the core of the Dane particle of hepatitis B. Am J Med Sci 1975;270:151–159CrossRefPubMedGoogle Scholar
  11. 11.
    Robinson WS, Lutwick LI. The virus of hepatitis, type B (first of two parts). N Engl J Med 1976;295:1168–1175CrossRefPubMedGoogle Scholar
  12. 12.
    Robinson WS, Lutwick LI. The virus of hepatitis, type B. (Second of two parts). N Engl J Med 1976;295:1232–1236CrossRefPubMedGoogle Scholar
  13. 13.
    Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 1981;2:1129–1133CrossRefPubMedGoogle Scholar
  14. 14.
    Szmuness W, Stevens CE, Zang EA, Harley EJ, Kellner A. A controlled clinical trial of the efficacy of the hepatitis B vaccine (Heptavax B): a final report. Hepatology 1981;1:377–385CrossRefPubMedGoogle Scholar
  15. 15.
    Karayiannis P, Main J, Thomas HC. Hepatitis vaccines. Br Med Bull 2004;70:29–49CrossRefPubMedGoogle Scholar
  16. 16.
    Lok AS, McMahon BJ, Brown RS Jr, Wong JB, Ahmed AT, Farah W et al. Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis. Hepatology 2016;63:284–306CrossRefPubMedGoogle Scholar
  17. 17.
    Zoulim F, Lebossé F, Levrero M. Current treatments for chronic hepatitis B virus infections. Curr Opin Virol 2016;18:109–116CrossRefPubMedGoogle Scholar
  18. 18.
    Locarnini SA, Roggendorf M. Other hepadnaviridae [Avihepadnaviridae (DHBV) and Orthohepadnaviridae (WHV)]. In: Thomas HC, Lok ASF, Locarnini SA, Zuckerman AJ, editors. Viral Hepatitis. 4th ed. Wiley-Blackwell: Oxford; 2014. p. 96–106Google Scholar
  19. 19.
    Kramvis A. Genotypes and genetic variability of hepatitis B virus. Intervirology 2014;57:141–150CrossRefPubMedGoogle Scholar
  20. 20.
    Tran TT, Trinh TN, Abe K. New complex recombinant genotype of hepatitis B virus identified in Vietnam. J Virol 2008;82:5657–5663CrossRefPubMedGoogle Scholar
  21. 21.
    Tatematsu K, Tanaka Y, Kurbanov F, Sugauchi F, Mano S, Maeshiro T et al. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J. J Virol 2009;83:10538–10547CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Pourkarim MR, Amini-Bavil-Olyaee S, Kurbanov F, Van Ranst M, Tacke F. Molecular identification of hepatitis B virus genotypes/subgenotypes: revised classification hurdles and updated resolutions. World J Gastroenterol 2014;20:7152–7168CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Araujo NM. Hepatitis B virus intergenotypic recombinants worldwide: an overview. Infect Genet Evol 2015;36:500–510CrossRefPubMedGoogle Scholar
  24. 24.
    Ganem D, Prince AM. Hepatitis B virus infection–natural history and clinical consequences. N Engl J Med 2004;350:1118–1129CrossRefPubMedGoogle Scholar
  25. 25.
    Kaplan PM, Greenman RL, Gerin JL, Purcell RH, Robinson WS. DNA polymerase associated with human hepatitis B antigen. J Virol 1973;12:995–1005PubMedPubMedCentralGoogle Scholar
  26. 26.
    Robinson WS, Clayton DA, Greenman RL. DNA of a human hepatitis B virus candidate. J Virol 1974;14:384–391PubMedPubMedCentralGoogle Scholar
  27. 27.
    Summers J, O’Connell A, Millman I. Genome of hepatitis B virus: restriction enzyme cleavage and structure of DNA extracted from Dane particles. Proc Natl Acad Sci USA 1975;72:4597–4601CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Baltayiannis G, Karayiannis P. Treatment options beyond IFNα and NUCs for chronic HBV infection: expectations for tomorrow. J Viral Hepatol 2014;21:753–761CrossRefPubMedGoogle Scholar
  29. 29.
    Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev 2000;4:51–68CrossRefGoogle Scholar
  30. 30.
    Quasdorff M, Protzer U. Control of hepatitis B virus at the level of transcription. J Viral Hepatol 2010;17:527–536CrossRefPubMedGoogle Scholar
  31. 31.
    Wang J, Lee AS, Ou JH. Proteolytic conversion of hepatitis B virus e antigen precursor to end product occurs in a postendoplasmic reticulum compartment. J Virol 1991;65:5080–5083PubMedPubMedCentralGoogle Scholar
  32. 32.
    Messageot F, Salhi S, Eon P, Rossignol JM. Proteolytic processing of the hepatitis B virus e antigen precursor. Cleavage at two furin consensus sequences. J Biol Chem 2003;278:891–895CrossRefPubMedGoogle Scholar
  33. 33.
    Ito K, Kim KH, Lok AS, Tong S. Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme. J Virol 2009;83:3507–3517CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Milich DR, Jones JE, Hughes JL, Price J, Raney AK, McLachlan A. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci USA 1990;87:6599–6603CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Crowther RA, Kiselev NA, Bottcher B, Berriman JA, Borisova GP, Ose V, Pumpens P. Three-dimensional structure of hepatitis B virus core particles determined by electron cryomicroscopy. Cell 1994;77:943–950CrossRefPubMedGoogle Scholar
  36. 36.
    Ganem D, Schneider RJ. Hepadnaviridae: the viruses and their replication. In: Knipe DM, Howley PM, editors. Fields virology, vol. 2. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2001. p. 2923–2969Google Scholar
  37. 37.
    Neurath AR, Kent SB, Strick N, Parker K. Identification and chemical synthesis of a host cell receptor binding site on hepatitis B virus. Cell 1986;46:429–436CrossRefPubMedGoogle Scholar
  38. 38.
    Gripon P, Cannie I, Urban S. Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol 2005;79:1613–1622CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Gripon P, Le Seyec J, Rumin S, Guguen-Guillouzo C. Myristylation of the hepatitis B virus large surface protein is essential for viral infectivity. Virology 1995;213:292–299CrossRefPubMedGoogle Scholar
  40. 40.
    Eble BE, MacRae DR, Lingappa VR, Ganem D. Multiple topogenic sequences determine the transmembrane orientation of the hepatitis B surface antigen. Mol Cell Biol 1987;7:3591–35601CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Bruss V. Hepatitis B virus morphogenesis. World J Gastroenterol 2007;13:65–73CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Slagle BL, Bouchard MJ. Hepatitis B Virus X and Regulation of Viral Gene Expression. Cold Spring Harb Perspect Med 2016;6:a021402CrossRefPubMedGoogle Scholar
  43. 43.
    Geng M, Xin X, Bi LQ, Zhou LT, Liu XH. Molecular mechanism of hepatitis B virus X protein function in hepatocarcinogenesis. World J Gastroenterol 2015;21:10732–10738CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z et al.. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 2012;1:e00049CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Blanchet M, Sureau C. Infectivity determinants of the hepatitis B virus pre-S domain are confined to the N-terminal 75 amino acid residues. J Virol 2007;81:5841–5849CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Schulze A, Gripon P, Urban S. Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology 2007;46:1759–1768CrossRefGoogle Scholar
  47. 47.
    Verrier ER, Colpitts CC, Bach C, Heydmann L, Weiss A, Renaud M et al. A targeted functional RNA interference screen uncovers glypican 5 as an entry factor for hepatitis B and D viruses. Hepatology 2016;63:35–48CrossRefPubMedGoogle Scholar
  48. 48.
    Huang HC, Chen CC, Chang WC, Tao MH, Huang C. Entry of hepatitis B virus into immortalized human primary hepatocytes by clathrin-dependent endocytosis. J Virol 2012;86:9443–9453CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Rabe B, Delaleau M, Bischof A, Foss M, Sominskaya I, Pumpens P et al. Nuclear entry of hepatitis B virus capsids involves disintegration to protein dimers followed by nuclear reassociation to capsids. PLoS Pathog 2009;5:e1000563CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Schmitz A, Schwarz A, Foss M, Zhou L, Rabe B, Hoellenriegel J et al. Nucleoporin 153 arrests the nuclear import of hepatitis B virus capsids in the nuclear basket. PLoS Pathog 2010;6:e1000741CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Tuttleman JS, Pourcel C, Summers J. Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell 1986;47:451–460CrossRefPubMedGoogle Scholar
  52. 52.
    Pollicino T, Belloni L, Raffa G, Pediconi N, Squadrito G, Raimondo G, Levrero M. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology 2006;130:823–837CrossRefPubMedGoogle Scholar
  53. 53.
    Belloni L, Pollicino T, Cimino L, Raffa G, Raimondo G, Levrero M. Nuclear HBx binds in vivo on the HBV minichromosome, modifies the epigenetic regulation of ccc-DNA function and potentiates HBV replication. J Hepatol 2008;48:s25CrossRefGoogle Scholar
  54. 54.
    Koumbi L, Karayiannis P. The epigenetic control of hepatitis B virus modulates the outcome of infection. Front Microbiol 2016;6:1491CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Kramvis A, Kew MC. Structure and function of the encapsidation signal of hepadnaviridae. J Viral Hepat 1998;5:357–367CrossRefPubMedGoogle Scholar
  56. 56.
    Summers J, Mason WS. Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 1982;29:403–415CrossRefPubMedGoogle Scholar
  57. 57.
    Karayiannis P. Hepatitis B virus: old, new and future approaches to antiviral treatment. J Antimicrob Chemother 2003;51:761–785CrossRefPubMedGoogle Scholar
  58. 58.
    Jeong JK, Yoon GS, Ryu WS. Evidence that the 5′-end cap structure is essential for encapsidation of hepatitis B virus pregenomic RNA. J Virol 2000;74(12):5502–5508CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Kim S, Wang H, Ryu WS. Incorporation of eukaryotic translation initiation factor eIF4E into viral nucleocapsids via interaction with hepatitis B virus polymerase. J Virol 2010;84:52–58CrossRefPubMedGoogle Scholar
  60. 60.
    Hu J, Toft DO, Seeger C. Hepadnavirus assembly and reverse transcription require a multi-component chaperone complex which is incorporated into nucleocapsids. EMBO J 1997;16:59–68CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Zlotnick A, Venkatakrishnan B, Tan Z, Lewellyn E, Turner W, Francis S. Core protein: a pleiotropic keystone in the HBV lifecycle. Antiviral Res 2015;121:82–93CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Nassal M, Rieger A. A bulged region of the hepatitis B virus RNA encapsidation signal contains the replication origin for discontinuous first-strand DNA synthesis. J Virol 1996;70:2764–2773PubMedPubMedCentralGoogle Scholar
  63. 63.
    Zoulim F, Seeger C. Reverse transcription in hepatitis B viruses is primed by a tyrosine residue of the polymerase. J Virol 1994;68:6–13PubMedPubMedCentralGoogle Scholar
  64. 64.
    Weber M, Bronsema V, Bartos H, Bosserhoff A, Bartenschlager R, Schaller H. Hepadnavirus P protein utilizes a tyrosine residue in the TP domain to prime reverse transcription. J Virol 1994;68:2994–2999PubMedPubMedCentralGoogle Scholar
  65. 65.
    Tang H, McLachlan A. A pregenomic RNA sequence adjacent to DR1 and complementary to epsilon influences hepatitis B virus replication efficiency. Virology 2002;303:199–210CrossRefPubMedGoogle Scholar
  66. 66.
    Abraham TM, Loeb DD. Base pairing between the 5′ half of epsilon and a cis-acting sequence, phi, makes a contribution to the synthesis of minus-strand DNA for human hepatitis B virus. J Virol 2006;80:4380–4387CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Haines KM, Loeb DD. The sequence of the RNA primer and the DNA template influence the initiation of plus-strand DNA synthesis of hepatitis B virus. J Mol Biol 2007;370:471–480CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Lewellyn EB, Loeb DD. Base pairing between cis-acting sequences contributes to template switching during plus-strand DNA synthesis in human hepatitis B virus. J Virol 2007;81:6207–6215CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Nassal M. Hepatitis B viruses: reverse transcription a different way. Virus Res 2008;134:235–249CrossRefPubMedGoogle Scholar
  70. 70.
    Lentz TB, Loeb DD. Roles of the envelope proteins in the amplification of covalently closed circular DNA and completion of synthesis of the plus-strand DNA in hepatitis B virus. J Virol 2011;85:11916–11927CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Gerelsaikhan T, Tavis JE, Bruss V. Hepatitis B virus nucleocapsid envelopment does not occur without genomic DNA synthesis. J Virol 1996;70:4269–4272PubMedPubMedCentralGoogle Scholar
  72. 72.
    Watanabe T, Sorensen EM, Naito A, Schott M, Kim S, Ahlquist P. Involvement of host cellular multivesicular body functions in hepatitis B virus budding. Proc Natl Acad Sci USA 2007;104:10205–10210CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Jilbert AR, Freiman JS, Burrell CJ, Holmes M, Gowans EJ, Rowland R, Hall P, Cossart YE. Virus-liver cell interactions in duck hepatitis B virus infection. A study of virus dissemination within the liver. Gastroenterology 1988;95:1375–1282CrossRefPubMedGoogle Scholar
  74. 74.
    Bertoletti A, Gehring AJ. The immune response during hepatitis B virus infection. J Gen Virol 2006;87:1439–1449CrossRefPubMedGoogle Scholar
  75. 75.
    Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000;191:1269–1280CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 2003;77:68–76CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    MacDonald RA. “Lifespan” of liver cells. Arch Intern Med 1960;107:335–343CrossRefGoogle Scholar
  78. 78.
    Thorgeirsson SS. Hepatic stem cells in liver regeneration. FASEB J 1996;10:1249–1256PubMedGoogle Scholar
  79. 79.
    Lutgehetmann M, Volz T, Köpke A, Broja T, Tigges E, Lohse AW et al. In vivo proliferation of hepadnavirus-infected hepatocytes induces loss of covalently closed circular DNA in mice. Hepatology 2010;52:16–24CrossRefPubMedGoogle Scholar
  80. 80.
    Sattentau Q. Avoiding the void: cell-to-cell spread of human viruses. Nat Rev Microbiol 2008;6:815–826CrossRefPubMedGoogle Scholar
  81. 81.
    Funk A, Hohenberg H, Mhamdi M, Will H, Sirma H. Spread of hepatitis B viruses in vitro requires extracellular progeny and may be codetermined by polarized egress. J Virol 2004;78:3977–3983CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Bhat P, Snooks MJ, Anderson DA. Hepatocytes traffic and export hepatitis B virus basolaterally by polarity-dependent mechanisms. J Virol 2011;85:12474–12481CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet 2012;21:R125–R134CrossRefGoogle Scholar
  84. 84.
    Timpe JM, Stamataki Z, Jennings A, Hu K, Farquhar MJ, et al. Hepatitis C virus cell-cell transmission in hepatoma cells in the presence of neutralising antibodies. Hepatology 2008;47:17–24CrossRefPubMedGoogle Scholar
  85. 85.
    Bukong TN, Momen-Heravi F, Kodys K, Bala S, Szabo G. Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90. PLoS Pathog 2014;10:e1004424CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Goyal A, Murray JM. Modelling the impact of cell-to-cell transmission in hepatitis B virus. PLoS One 2016;11:e0161978CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2017

Authors and Affiliations

  1. 1.Medical SchoolUniversity of NicosiaNicosiaCyprus

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