Skip to main content

HBV Genome and Life Cycle

  • Chapter
  • First Online:
Hepatitis B Virus Infection

Abstract

Chronic hepatitis B virus (HBV) infection remains to be a serious threat to public health and is associated with many liver diseases including chronic hepatitis B (CHB), liver cirrhosis, and hepatocellular carcinoma. Although nucleos(t)ide analogues (NA) and pegylated interferon-α (Peg-IFNα) have been confirmed to be efficient in inhibiting HBV replication, it is difficult to eradicate HBV and achieve the clinical cure of CHB. Therefore, long-term therapy has been recommended to CHB treatment under the current antiviral therapy. In this context, the new antiviral therapy targeting one or multiple critical steps of viral life cycle may be an alternative approach in future. In the last decade, the functional receptor [sodium-taurocholate cotransporting polypeptide (NTCP)] of HBV entry into hepatocytes has been discovered, and the immature nucleocapsids containing the non- or partially reverse-transcribed pregenomic RNA, the nucleocapsids containing double-strand linear DNA (dslDNA), and the empty particles devoid of any HBV nucleic acid have been found to be released into circulation, which have supplemented the life cycle of HBV. The understanding of HBV life cycle may offer a new instruction for searching the potential antiviral targets, and the new viral markers used to monitor the efficacy of antiviral therapy for CHB patients in the future.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. GBD (2018) Causes of death collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the global burden of disease study 2017. Lancet 392(10159):1736–1788

    Google Scholar 

  2. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ (2015) Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet 386(10003):1546–1555

    Article  PubMed  Google Scholar 

  3. World Health Organization. Hepatitis B 2018 [Available from: http://www.who.int/news-room/fact-sheets/detail/hepatitis-b]

  4. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G et al (2005) Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 352(26):2682–2695

    Article  CAS  PubMed  Google Scholar 

  5. Wei L, Kao JH (2017) Benefits of long-term therapy with nucleos(t)ide analogues in treatment-naïve patients with chronic hepatitis B. Curr Med Res Opin 33(3):495–504

    Article  CAS  PubMed  Google Scholar 

  6. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ et al (2016) Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 10(1):1–98

    Article  CAS  PubMed  Google Scholar 

  7. European Association for the Study of the Liver (2017) EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 67(2):370–398

    Article  Google Scholar 

  8. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM et al (2018) Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 67(4):1560–1599

    Article  PubMed  Google Scholar 

  9. Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J et al (2017) Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 11(4):317–370

    Article  PubMed  Google Scholar 

  10. Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z et al (2012) Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. elife 13:3

    Google Scholar 

  11. Blank A, Markert C, Hohmann N, Carls A, Mikus G, Lehr T et al (2016) First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol 65:483–489

    Article  CAS  PubMed  Google Scholar 

  12. Urban S, Bartenschlager R, Kubitz R, Zoulim F (2014) Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology 147:48–64

    Article  CAS  PubMed  Google Scholar 

  13. Zimmerman KA, Fischer KP, Joyce MA, Tyrrell DL (2008) Zinc finger proteins designed to specifically target duck hepatitis B virus covalently closed circular DNA inhibit viral transcription in tissue culture. J Virol 82:8013–8021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cradick TJ, Keck K, Bradshaw S, Jamieson AC, McCaffrey AP (2010) Zinc-finger nucleases as a novel therapeutic strategy for targeting hepatitis B virus DNAs. Mol Ther 18:947–954

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bloom K, Ely A, Mussolino C, Cathomen T, Arbuthnot P (2013) Inactivation of hepatitis B virus replication in cultured cells and in vivo with engineered transcription activator-like effector nucleases. Mol Ther 21:1889–1897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chen J, Zhang W, Lin J, Wang F, Wu M, Chen C et al (2014) An efficient antiviral strategy for targeting hepatitis B virus genome using transcription activator-like effector nucleases. Mol Ther 22:303–311

    Article  PubMed  CAS  Google Scholar 

  17. Lin SR, Yang HC, Kuo YT, Liu CJ, Yang TY, Sung KC et al (2014) The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo. Mol Ther Nucleic Acids 3:e186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhen S, Hua L, Liu YH, Gao LC, Fu J, Wan DY et al (2015) Harnessing the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated Cas9 system to disrupt the hepatitis B virus. Gene Ther 22:404–412

    Article  CAS  PubMed  Google Scholar 

  19. Wang J, Xu ZW, Liu S, Zhang RY, Ding SL, Xie XM et al (2015) Dual gRNAs guided CRISPR/Cas9 system inhibits hepatitis B virus replication. World J Gastroenterol 21:9554–9565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang J, Chen R, Zhang R, Ding S, Zhang T, Yuan Q et al (2017) The gRNA-miRNA-gRNA ternary cassette combining CRISPR/Cas9 with RNAi approach Strongly Inhibits hepatitis B virus replication. Theranostics 7:3090–3105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gish RG, Yuen MF, Chan HL, Given BD, Lai CL, Locarnini SA et al (2015) Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent. Antivir Res 121:97–108

    Article  CAS  PubMed  Google Scholar 

  22. Yuen M-F, Chan HLY, Liu K, Given BD, Schluep T, Hamilton J et al (2016) Differential reductions in viral antigens expressed from cccDNA vs integrated DNA in treatment naive HBeAg positive and negative patients with chronic HBV after RNA interference therapy with ARC-520. J Hepatol 64:213

    Google Scholar 

  23. Klumpp K, Lam AM, Lukacs C, Vogel R, Ren S, Espiritu C et al (2015) High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein. Proc Natl Acad Sci U S A 112:15196–15201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Venkatakrishnan B, Katen SP, Francis S, Chirapu S, Finn MG, Zlotnick A (2016) Hepatitis B virus capsids have diverse structural responses to small-molecule ligands bound to the heteroaryldihydropyrimidine pocket. J Virol 90:3994–4004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yuen M-F, Kim DJ, Weilert F, Chan HL-Y, Lalezari J, Hwang SG et al (2016) NVR 3–778, a first-in-class HBV core inhibitor, alone and in combination with peg-interferon (PegIFN), in treatment naive HBeAg-positive patients: early reductions in HBV DNA and HBeAg. J Hepatol 64:LB-06

    Google Scholar 

  26. Lahlali T, Berke JM, Vergauwen K, Foca A, Vandyck K, Pauwels F et al (2018) Novel potent capsid assembly modulators regulate multiple steps of the hepatitis B virus life cycle. Antimicrob Agents Chemother 62(10):pii: e00835-18

    Article  Google Scholar 

  27. Lam AM, Espiritu C, Vogel R, Ren S, Lau V, Kelly M et al (2018) Preclinical characterization of NVR 3-778, a first-in-class capsid assembly modulator against hepatitis B virus. Antimicrob Agents Chemother 63(1):pii: e01734-18.

    Article  Google Scholar 

  28. Sato S, Li K, Kameyama T, Hayashi T, Ishida Y, Murakami S et al (2015) The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity 42:123–132

    Article  CAS  PubMed  Google Scholar 

  29. Korolowicz KE, Iyer RP, Czerwinski S, Suresh M, Yang J, Padmanabhan S et al (2016) Antiviral efficacy and host innate immunity associated with SB 9200 treatment in the woodchuck model of chronic hepatitis B. PLoS One 11:e0161313

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Wang L, Cao X, Wang Z, Gao Y, Deng J, Liu X et al (2019) Correlation of HBcrAg with intrahepatic hepatitis B virus Total DNA and covalently closed circular DNA in HBeAg-positive chronic hepatitis B patients. J Clin Microbiol 57(1):pii: e01303-18

    Article  Google Scholar 

  31. Loggi E, Vukotic R, Conti F, Grandini E, Gitto S, Cursaro C et al (2018) Serum hepatitis B core-related antigen is an effective tool to categorize patients with HBeAg-negative chronic hepatitis B. J Viral Hepat 26(5):568–575

    Article  CAS  Google Scholar 

  32. Testoni B, Lebossé F, Scholtes C, Berby F, Miaglia C, Subic M et al (2018) Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients. J Hepatol. pii: S0168-8278(18)32582-0

    Google Scholar 

  33. Liao H, Liu Y, Li X, Wang J, Chen X, Zou J et al (2018) Monitoring of serum HBV RNA, HBcrAg, HBsAg and anti-HBc levels in patients during long-term nucleoside/nucleotide analogue therapy. Antivir Ther 24(2):105–115

    Article  Google Scholar 

  34. Köck J, Theilmann L, Galle P, Schlicht HJ (1996) Hepatitis B virus nucleic acids associated with human peripheral blood mononuclear cells do not originate from replicating virus. Hepatology 23:405–413

    PubMed  Google Scholar 

  35. Jansen L, Kootstra NA, van Dort KA, Takkenberg RB, Reesink HW, Zaaijer HL (2016) Hepatitis B virus pregenomic RNA is present in virions in plasma and is associated with a response to pegylated interferon alfa-2a and nucleos(t)ide analogues. J Infect Dis 213(2):224–232

    Article  CAS  PubMed  Google Scholar 

  36. Wang J, Shen T, Huang X, Kumar GR, Chen X, Zeng Z et al (2016) Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J Hepatol 65(4):700–710

    Article  CAS  PubMed  Google Scholar 

  37. Butler EK, Gersch J, McNamara A, Luk KC, Holzmayer V, de Medina M et al (2018) Hepatitis B virus serum DNA and RNA levels in Nucleos(t)ide analog-treated or untreated patients during chronic and acute infection. Hepatology 68(6):2106–2117

    Article  CAS  PubMed  Google Scholar 

  38. van Bommel F, Bartens A, Mysickova A, Hofmann J, Kruger DH, Berg T et al (2015) Serum hepatitis B virus RNA levels as an early predictor of hepatitis B envelope antigen seroconversion during treatment with polymerase inhibitors. Hepatology 61:66–76

    Article  PubMed  CAS  Google Scholar 

  39. Zhao XL, Yang JR, Lin SZ, Ma H, Guo F, Yang RF et al (2016) Serum viral duplex-linear DNA proportion increases with the progression of liver disease in patients infected with HBV. Gut 65(3):502–511

    Article  CAS  PubMed  Google Scholar 

  40. Lamontagne RJ, Bagga S, Bouchard MJ (2016) Hepatitis B virus molecular biology and pathogenesis. Hepatoma Res 2:163–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Glebe D, Bremer CM (2013) The molecular virology of hepatitis B virus. Semin Liver Dis 33(2):103–112

    Article  CAS  PubMed  Google Scholar 

  42. Nassal M (1999) Hepatitis B virus replication: novel roles for virus-host interactions. Intervirology 42(2–3):100–116

    Article  CAS  PubMed  Google Scholar 

  43. Wei Y, Neuveut C, Tiollais P, Buendia MA (2010) Molecular biology of the hepatitis B virus and role of the X gene. Pathol Biol (Paris) 58(4):267–272

    Article  CAS  Google Scholar 

  44. Karayiannis P (2017) Hepatitis B virus: virology, molecular biology, life cycle and intrahepatic spread. Hepatol Int 11(6):500–508

    Article  CAS  PubMed  Google Scholar 

  45. Hao R, Xiang K, Peng Y, Hou J, Sun J, Li Y et al (2015) Naturally occurring deletion/insertion mutations within HBV whole genome sequences in HBeAg-positive chronic hepatitis B patients are correlated with baseline serum HBsAg and HBeAg levels and might predict a shorter interval to HBeAg loss and seroconversion during antiviral treatment. Infect Genet Evol 33:261–268

    Article  CAS  PubMed  Google Scholar 

  46. Tong S, Revill P (2016) Overview of hepatitis B viral replication and genetic variability. J Hepatol 64(1):S4–S16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kim DH, Kang HS, Kim KH (2016) Roles of hepatocyte nuclear factors in hepatitis B virus infection. World J Gastroenterol 22(31):7017–7029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Moolla N, Kew M, Arbuthnot P (2002) Regulatory elements of hepatitis B virus transcription. J Viral Hepat 9(5):323–331

    Article  PubMed  Google Scholar 

  49. Quarleri J (2014) Core promoter: a critical region where the hepatitis B virus makes decisions. World J Gastroenterol 20(2):425–435

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Zlotnick A, Venkatakrishnan B, Tan Z, Lewellyn E, Turner W, Francis S (2015) Core protein: a pleiotropic keystone in the HBV lifecycle. Antivir Res 121:82–93

    Article  CAS  PubMed  Google Scholar 

  51. Clark DN, Hu J (2015) Unveiling the roles of HBV polymerase for new antiviral strategies. Futur Virol 10(3):283–295

    Article  CAS  Google Scholar 

  52. Ganem D, Schneider RJ (2001) Hepadnaviridae: the viruses and their replication. In: Knipe DM, Howley PM (eds) Fields virology, vol 2, 4th edn. Lippincott Williams & Wilkins, Philadelphia, pp 2923–2969

    Google Scholar 

  53. Jones SA, Hu J (2013) Hepatitis B virus reverse transcriptase: diverse functions as classical and emerging targets for antiviral intervention. Emerg Microbes Infect 2(9):e56

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Nassal M (2008) Hepatitis B viruses: reverse transcription a different way. Virus Res 134(1–2):235–249

    Article  CAS  PubMed  Google Scholar 

  55. Venkatakrishnan B, Zlotnick A (2016) The structural biology of hepatitis B virus: form and function. Annu Rev Virol 3(1):429–451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chen MT, Billaud JN, Sällberg M, Guidotti LG, Chisari FV, Jones J et al (2004) A function of the hepatitis B virus precore protein is to regulate the immune response to the core antigen. Proc Natl Acad Sci U S A 101(41):14913–14918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ou JH, Laub O, Rutter WJ (1986) Hepatitis B virus gene function: the precore region targets the core antigen to cellular membranes and causes the secretion of the e antigen. Proc Natl Acad Sci U S A 83(6):1578–1582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sheu SY, Lo SJ (1992) Preferential ribosomal scanning is involved in the differential synthesis of the hepatitis B viral surface antigens from subgenomic transcripts. Virology 188(1):353–357

    Article  CAS  PubMed  Google Scholar 

  59. Quasdorff M, Protzer U (2010) Control of hepatitis B virus at the level of transcription. J Viral Hepat 17(8):527–536

    Article  CAS  PubMed  Google Scholar 

  60. Huan B, Siddiqui A (1993) Regulation of hepatitis B virus gene expression. J Hepatol 17(Suppl 3):S20–S23

    Article  CAS  PubMed  Google Scholar 

  61. Li Y, Ito M, Sun S, Chida T, Nakashima K, Suzuki T (2016) LUC7L3/CROP inhibits replication of hepatitis B virus via suppressing enhancer II/basal core promoter activity. Sci Rep 6:36741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhang Q, Cao G (2011) Genotypes, mutations, and viral load of hepatitis B virus and the risk of hepatocellular carcinoma: HBV properties and hepatocarcinogenesis. Hepat Mon 11(2):86–91

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Sureau C, Salisse J (2013) A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus a-determinant. Hepatology 57(3):985–994

    Article  CAS  PubMed  Google Scholar 

  64. Glebe D, Urban S, Knoop EV, Cag N, Krass P, Grün S et al (2005) Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and tupaia hepatocytes. Gastroenterology 129(1):234–245

    Article  CAS  PubMed  Google Scholar 

  65. Gripon P, Le Seyec J, Rumin S, Guguen-Guillouzo C (1995) Myristylation of the hepatitis B virus large surface protein is essential for viral infectivity. Virology 213(2):292–299

    Article  CAS  PubMed  Google Scholar 

  66. Bruss V, Hagelstein J, Gerhardt E, Galle PR (1996) Myristylation of the large surface protein is required for hepatitis B virus in vitro infectivity. Virology 218(2):396–399

    Article  CAS  PubMed  Google Scholar 

  67. De Falco S, Ruvo M, Verdoliva A, Scarallo A, Raimondo D, Raucci A et al (2001) N-terminal myristylation of HBV preS1 domain enhances receptor recognition. J Pept Res 57(5):390–400

    Article  PubMed  Google Scholar 

  68. Yan H, Peng B, He W, Zhong G, Qi Y, Ren B et al (2013) Molecular determinants of hepatitis B and D virus entry restriction in mouse sodium taurocholate cotransporting polypeptide. J Virol 87(14):7977–7991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Huang HC, Chen CC, Chang WC, Tao MH, Huang C (2012) Entry of hepatitis B virus into immortalized human primary hepatocytes by clathrin-dependent endocytosis. J Virol 86(17):9443–9453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Cooper A, Shaul Y (2006) Clathrin-mediated endocytosis and lysosomal cleavage of hepatitis B virus capsid-like core particles. J Biol Chem 281(24):16563–16569

    Article  CAS  PubMed  Google Scholar 

  71. Macovei A, Radulescu C, Lazar C, Petrescu S, Durantel D, Dwek RA et al (2010) Hepatitis B virus requires intact caveolin-1 function for productive infection in HepaRG cells. J Virol 84(1):243–253

    Article  CAS  PubMed  Google Scholar 

  72. Blondot ML, Bruss V, Kann M (2016) Intracellular transport and egress of hepatitis B virus. J Hepatol 64(1 Suppl):S49–S59

    Article  CAS  PubMed  Google Scholar 

  73. Zeyen L, Prange R (2018) Host cell Rab GTPases in hepatitis B virus infection. Front Cell Dev Biol 6:154

    Article  PubMed  PubMed Central  Google Scholar 

  74. Hayes CN, Zhang Y, Makokha GN, Hasan MZ, Omokoko MD, Chayama K (2016) Early events in hepatitis B virus infection: from the cell surface to the nucleus. J Gastroenterol Hepatol 31(2):302–309

    Article  CAS  PubMed  Google Scholar 

  75. Funk A, Mhamdi M, Hohenberg H, Will H, Sirma H (2006) pH-independent entry and sequential endosomal sorting are major determinants of hepadnaviral infection in primary hepatocytes. Hepatology 44(3):685–693

    Article  CAS  PubMed  Google Scholar 

  76. Funk A, Mhamdi M, Hohenberg H, Heeren J, Reimer R, Lambert C et al (2008) Duck hepatitis B virus requires cholesterol for endosomal escape during virus entry. J Virol 82(21):10532–10542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rabe B, Glebe D, Kann M (2006) Lipid-mediated introduction of hepatitis B virus capsids into nonsusceptible cells allows highly efficient replication and facilitates the study of early infection events. J Virol 80 (11): 5465–5473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Li HC, Huang EY, Su PY, Wu SY, Yang CC, Lin YS et al (2010) Nuclear export and import of human hepatitis B virus capsid protein and particles. PLoS Pathog 6(10):e1001162

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Schmitz A, Schwarz A, Foss M, Zhou L, Rabe B, Hoellenriegel J et al (2010) Nucleoporin 153 arrests the nuclear import of hepatitis B virus capsids in the nuclear basket. PLoS Pathog 6(1):e1000741

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Rabe B, Delaleau M, Bischof A, Foss M, Sominskaya I, Pumpens P et al (2009) Nuclear entry of hepatitis B virus capsids involves disintegration to protein dimers followed by nuclear reassociation to capsids. PLoS Pathog 5(8):e1000563

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Michael N (2015) HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 64(12):1972–1984

    Article  CAS  Google Scholar 

  82. Schreiner S, Nassal M (2017) A role for the host DNA damage response in hepatitis B virus cccDNA formation-and beyond? Viruses 9(5):125

    Article  PubMed Central  CAS  Google Scholar 

  83. Guo JT, Guo H (2015) Metabolism and function of hepatitis B virus cccDNA: implications for the development of cccDNA-targeting antiviral therapeutics. Antivir Res 122:91–100

    Article  CAS  PubMed  Google Scholar 

  84. Cui X, McAllister R, Boregowda R, Sohn JA, Cortes Ledesma F, Caldecott KW (2015) Does Tyrosyl DNA Phosphodiesterase-2 play a role in hepatitis B virus genome repair? PLoS One 10(6):e0128401

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Jones SA, Boregowda R, Spratt TE, Hu J (2012) In vitro epsilon RNA-dependent protein priming activity of human hepatitis B virus polymerase. J Virol 86(9):5134–5150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Jones SA, Hu J (2013) Protein-primed terminal transferase activity of hepatitis B virus polymerase. J Virol 87(5):2563–2576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Königer C, Wingert I, Marsmann M, Rösler C, Beck J, Nassal M (2014) Involvement of the host DNA-repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses. Proc Natl Acad Sci U S A 111(40):E4244–E4253

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Gao W, Hu J (2007) Formation of hepatitis B virus covalently closed circular DNA: removal of genome-linked protein. J Virol 81(12):6164–6174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Seeger C, Mason WS (2015) Molecular biology of hepatitis B virus infection. Virology 479–480:672–686

    Article  CAS  PubMed  Google Scholar 

  90. Kitamura K, Que L, Shimadu M, Koura M, Ishihara Y, Wakae K et al (2018) Flap endonuclease 1 is involved in cccDNA formation in the hepatitis B virus. PLoS Pathog 14(6):e1007124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Hantz O, Parent R, Durantel D, Gripon P, Guguen-Guillouzo C, Zoulim F (2009) Persistence of the hepatitis B virus covalently closed circular DNA in HepaRG human hepatocyte-like cells. J Gen Virol 90(Pt 1):127–135

    Article  CAS  PubMed  Google Scholar 

  92. Qi Y, Gao Z, Xu G, Peng B, Liu C, Yan H et al (2016) DNA polymerase κ is a key cellular factor for the formation of covalently closed circular DNA of hepatitis B virus. PLoS Pathog 12(10):e1005893

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Long Q, Yan R, Hu J, Cai D, Mitra B, Kim ES et al (2017) The role of host DNA ligases in hepadnavirus covalently closed circular DNA formation. PLoS Pathog 13(12):e1006784

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Guo H, Xu C, Zhou T, Block TM, Guo JT (2012) Characterization of the host factors required for hepadnavirus covalently closed circular (ccc) DNA formation. PLoS One 7(8):e43270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chang HHY, Pannunzio NR, Adachi N, Lieber MR (2017) Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol 18(8):495–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Newbold JE, Xin H, Tencza M, Sherman G, Dean J, Bowden S et al (1995) The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minichromosomes. J Virol 69(6):3350–3357

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Bock CT, Schwinn S, Locarnini S, Fyfe J, Manns MP, Trautwein C et al (2001) Structural organization of the hepatitis B virus minichromosome. J Mol Biol 307(1):183–196

    Article  CAS  PubMed  Google Scholar 

  98. Hong X, Kim ES, Guo H (2017) Epigenetic regulation of hepatitis B virus covalently closed circular DNA: implications for epigenetic therapy against chronic hepatitis B. Hepatology 66(6):2066–2077

    Article  CAS  PubMed  Google Scholar 

  99. Nassal M, Schaller H (1993) Hepatitis B virus replication. Trends Microbiol 1(6):221–228

    Article  CAS  PubMed  Google Scholar 

  100. Kitamura K, Que L, Shimadu M, Koura M, Ishihara Y, Wakae K et al (2018) Flap endonuclease 1 is involved in cccDNA formation in the hepatitis B virus. PLoS Pathog 14(6):e1007124

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Hu J, Cheng J, Tang L, Hu Z, Luo Y, Li Y et al (2018) Virological basis for the cure of chronic hepatitis B. ACS Infect Dis 5(5):659–674

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  102. Kramvis A, Kew MC (1999) The core promoter of hepatitis B virus. J Viral Hepat 6(6):415–427

    Article  CAS  PubMed  Google Scholar 

  103. Kairat A, Beerheide W, Zhou G, Tang ZY, Edler L, Schröder CH (1999) Truncated hepatitis B virus RNA in human hepatocellular carcinoma: its representation in patients with advancing age. Intervirology 42(4):228–237

    Article  CAS  PubMed  Google Scholar 

  104. Lu F, Wang J, Chen X, Xu D, Xia N (2017) Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos(t)ide analogs. Front Med 11(4):502–508

    Article  PubMed  Google Scholar 

  105. Hiraga M, Nishizono A, Mifune K, Esumi M, Shikata T (1994) Analysis of upstream region of hepatitis B virus core gene using in vitro transcription system. J Med Virol 43(4):404–411

    Article  CAS  PubMed  Google Scholar 

  106. Yu X, Mertz JE (1996) Promoters for synthesis of the pre-C and pregenomic mRNAs of human hepatitis B virus are genetically distinct and differentially regulated. J Virol 70(12):8719–8726

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Yuh CH, Chang YL, Ting LP (1992) Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus. J Virol 66(7):4073–4084

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Guo W, Chen M, Yen TS, Ou JH (1993) Hepatocyte-specific expression of the hepatitis B virus core promoter depends on both positive and negative regulation. Mol Cell Biol 13(1):443–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gerlach KK, Schloemer RH (1992) Hepatitis B virus C gene promoter is under negative regulation. Virology 189(1):59–66

    Article  CAS  PubMed  Google Scholar 

  110. Will H, Reiser W, Weimer T, Pfaff E, Büscher M, Sprengel R et al (1987) Replication strategy of human hepatitis B virus. J Virol 61(3):904–911

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Caselmann WH, Koshy R (1998) Transactivators of HBV, signal transduction and tumorigenesis Caselmann. In: Caselmann W, Koshy R (eds) Hepatitis b virus: molecular mechanisms in disease and novel strategies for therapy, vol 1. Imperial College Press, London, pp 161–181

    Chapter  Google Scholar 

  112. Sommer G, Heise T (2008) Posttranscriptional control of HBV gene expression. Front Biosci 13:5533–5547

    Article  CAS  PubMed  Google Scholar 

  113. Black DL (2003) Mechanisms of alternative pre-messenger RNA splicing. Annu Rev Biochem 72:291–336

    Article  CAS  PubMed  Google Scholar 

  114. Su TS, Lai CJ, Huang JL, Lin LH, Yauk YK, Chang CM et al (1989) Hepatitis B virus transcript produced by RNA splicing. J Virol 63(9):4011–4018

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Terré S, Petit MA, Bréchot C (1991) Defective hepatitis B virus particles are generated by packaging and reverse transcription of spliced viral RNAs in vivo. J Virol 65(10):5539–5543

    PubMed  PubMed Central  Google Scholar 

  116. Bayliss J, Lim L, Thompson AJ, Desmond P, Angus P, Locarnini S et al (2013) Hepatitis B virus splicing is enhanced prior to development of hepatocellular carcinoma. J Hepatol 59:1022–1028

    Article  CAS  PubMed  Google Scholar 

  117. Redelsperger F, Lekbaby B, Mandouri Y, Giang E, Duriez M, Desire N et al (2012) Production of hepatitis B defective particles is dependent on liver status. Virology 431:21–28

    Article  CAS  PubMed  Google Scholar 

  118. Soussan P, Pol J, Garreau F, Schneider V, Le Pendeven C, Nalpas B et al (2008) Expression of defective hepatitis B virus particles derived from singly spliced RNA is related to liver disease. J Infect Dis 198(2):218–225

    Article  CAS  PubMed  Google Scholar 

  119. Duriez M, Mandouri Y, Lekbaby B, Wang H, Schnuriger A, Redelsperger F et al (2017) Alternative splicing of hepatitis B virus: a novel virus/host interaction altering liver immunity. J Hepatol 67:687–699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Soussan P, Garreau F, Zylberberg H, Ferray C, Brechot C, Kremsdorf D (2000) In vivo expression of a new hepatitis B virus protein encoded by a spliced RNA. J Clin Invest 105:55–60

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Bayard F, Godon O, Nalpas B, Costentin C, Zhu R, Soussan P et al (2012) T-cell responses to hepatitis B splice-generated protein of hepatitis B virus and inflammatory cytokines/chemokines in chronic hepatitis B patients. ANRS study: HB EP 02 HBSP-FIBRO. J Viral Hepat 19:872–880

    Article  CAS  PubMed  Google Scholar 

  122. Chen JY, Chen WN, Jiao BY, Lin WS, Wu YL, Liu LL et al (2014) Hepatitis B spliced protein (HBSP) promotes the carcinogenic effects of benzo [alpha] pyrene by interacting with microsomal epoxide hydrolase and enhancing its hydrolysis activity. BMC Cancer 14:282

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Pol JG, Lekbaby B, Redelsperger F, Klamer S, Mandouri Y, Ahodantin J et al (2015) Alternative splicing-regulated protein of hepatitis B virus hacks the TNF-alpha-stimulated signaling pathways and limits the extent of liver inflammation. FASEB J 29:1879–1889

    Article  CAS  PubMed  Google Scholar 

  124. Bruss V, Gerlich WH (1988) Formation of transmembraneous hepatitis B e-antigen by cotranslational in vitro processing of the viral precore protein. Virology 163:268–275

    Article  CAS  PubMed  Google Scholar 

  125. Bruss V (2007) Hepatitis B virus morphogenesis. World J Gastroenterol 13:65–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Chai N, Chang HE, Nicolas E, Han Z, Jarnik M, Taylor J (2008) Properties of subviral particles of hepatitis B virus. J Virol 82:7812–7817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Cornberg M, Wong VW, Locarnini S, Brunetto M, Janssen HLA, Chan HL (2017) The role of quantitative hepatitis B surface antigen revisited. J Hepatol 66:398–411

    Article  CAS  PubMed  Google Scholar 

  128. Glebe D, Urban S (2007) Viral and cellular determinants involved in hepadnaviral entry. World J Gastroenterol 13:22–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Gudima S, He Y, Meier A, Chang J, Chen R, Jarnik M et al (2007) Assembly of hepatitis delta virus: particle characterization, including the ability to infect primary human hepatocytes. J Virol 81:3608–3617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Heermann KH, Goldmann U, Schwartz W, Seyffarth T, Baumgarten H, Gerlich WH (1984) Large surface proteins of hepatitis B virus containing the pre-s sequence. J Virol 52:396–402

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Huovila AP, Eder AM, Fuller SD (1992) Hepatitis B surface antigen assembles in a post-ER, pre-Golgi compartment. J Cell Biol 118:1305–1320

    Article  CAS  PubMed  Google Scholar 

  132. Jiang B, Himmelsbach K, Ren H, Boller K, Hildt E (2015) Subviral hepatitis B virus filaments, like infectious viral particles, are released via multivesicular bodies. J Virol 90:3330–3341

    Article  PubMed  CAS  Google Scholar 

  133. Lok AS, Zoulim F, Dusheiko G, Ghany MG (2017) Hepatitis B cure: from discovery to regulatory approval. J Hepatol 67:847–861

    Article  PubMed  Google Scholar 

  134. Lok AS, Zoulim F, Dusheiko G, Ghany MG (2017) Hepatitis B cure: from discovery to regulatory approval. Hepatology 66:1296–1313

    Article  PubMed  Google Scholar 

  135. Murakami S (2001) Hepatitis B virus X protein: a multifunctional viral regulator. J Gastroenterol 36:651–660

    Article  CAS  PubMed  Google Scholar 

  136. Murakami S (1999) Hepatitis B virus X protein: structure, function and biology. Intervirology 42:81–99

    Article  CAS  PubMed  Google Scholar 

  137. Beck J, Vogel M, Nassal M (2002) dNTP versus NTP discrimination by phenylalanine 451 in duck hepatitis B virus P protein indicates a common structure of the dNTP-binding pocket with other reverse transcriptases. Nucleic Acids Res 30(7):1679–1687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Tavis JE, Massey B, Gong Y (1998) The duck hepatitis B virus polymerase is activated by its RNA packaging signal, epsilon. J Virol 72(7):5789–5796

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Tavis JE, Ganem D (1996) Evidence for activation of the hepatitis B virus polymerase by binding of its RNA template. J Virol 70(9):5741–5750

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Junker-Niepmann M, Bartenschlager R, Schaller H (1990) A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA. EMBO J 9(10):3389–3396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kim HY, Park GS, Kim EG, Kang SH, Shin HJ, Park S et al (2004) Oligomer synthesis by priming deficient polymerase in hepatitis B virus core particle. Virology 322(1):22–30

    Article  CAS  PubMed  Google Scholar 

  142. Hu J, Toft DO, Seeger C (1997) Hepadnavirus assembly and reverse transcription require a multi-component chaperone complex which is incorporated into nucleocapsids. EMBO J 16(1):59–68

    Article  PubMed  PubMed Central  Google Scholar 

  143. Hu J, Seeger C (1996) Hsp90 is required for the activity of a hepatitis B virus reverse transcriptase. Proc Natl Acad Sci U S A 93(3):1060–1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Patel N, White SJ, Thompson RF, Bingham R, Weiss EU, Maskell DP et al (2017) HBV RNA pre-genome encodes specific motifs that mediate interactions with the viral core protein that promote nucleocapsid assembly. Nat Microbiol 2:17098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Wang GH, Seeger C (1992) The reverse transcriptase of hepatitis B virus acts as a protein primer for viral DNA synthesis. Cell 71(4):663–670

    Article  CAS  PubMed  Google Scholar 

  146. Lanford RE, Notvall L, Lee H, Beames B (1997) Transcomplementation of nucleotide priming and reverse transcription between independently expressed TP and RT domains of the hepatitis B virus reverse transcriptase. J Virol 71(4):2996–3004

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Weber M, Bronsema V, Bartos H, Bosserhoff A, Bartenschlager R, Schaller H (1994) Hepadnavirus P protein utilizes a tyrosine residue in the TP domain to prime reverse transcription. J Virol 68(5):2994–2999

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Zoulim F, Seeger C (1994) Reverse transcription in hepatitis B viruses is primed by a tyrosine residue of the polymerase. J Virol 68(1):6–13

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Tavis JE, Ganem D (1995) RNA sequences controlling the initiation and transfer of duck hepatitis B virus minus-strand DNA. J Virol 69(7):4283–4291

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Tavis JE, Perri S, Ganem D (1994) Hepadnavirus reverse transcription initiates within the stem-loop of the RNA packaging signal and employs a novel strand transfer. J Virol 68(6):3536–3543

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Wang GH, Seeger C (1993) Novel mechanism for reverse transcription in hepatitis B viruses. J Virol 67(11):6507–6512

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Abraham TM, Loeb DD (2006) 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 80(9):4380–4387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Tang H, Mclachlan A (2002) A pregenomic RNA sequence adjacent to DR1 and complementary to epsilon influences hepatitis B virus replication efficiency. Virology 303(1):199–210

    Article  CAS  PubMed  Google Scholar 

  154. Abraham TM, Loeb DD (2007) The topology of hepatitis B virus pregenomic RNA promotes its replication. J Virol 81(21):11577–11584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Haines KM, Loeb DD (2007) The sequence of the RNA primer and the DNA template influence the initiation of plus-strand DNA synthesis in hepatitis B virus. J Mol Biol 370(3):471–480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Loeb DD, Hirsch RC, Ganem D (1991) Sequence-independent RNA cleavages generate the primers for plus strand DNA synthesis in hepatitis B viruses: implications for other reverse transcribing elements. EMBO J 10(11):3533–3540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Summers J, Mason WS (1982) Replication of the genome of a hepatitis B--like virus by reverse transcription of an RNA intermediate. Cell 29(2):403–415

    Article  CAS  PubMed  Google Scholar 

  158. Seeger C, Ganem D, Varmus HE (1986) Biochemical and genetic evidence for the hepatitis B virus replication strategy. Science 232(4749):477–484

    Article  CAS  PubMed  Google Scholar 

  159. Lien JM, Aldrich CE, Mason WS (1986) Evidence that a capped oligoribonucleotide is the primer for duck hepatitis B virus plus-strand DNA synthesis. J Virol 57(1):229–236

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Habig JW, Loeb DD (2006) Sequence identity of the direct repeats, DR1 and DR2, contributes to the discrimination between primer translocation and in situ priming during replication of the duck hepatitis B virus. J Mol Biol 364(1):32–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Yang W, Summers J (1999) Integration of hepadnavirus DNA in infected liver: evidence for a linear precursor. J Virol 73(12):9710–9717

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Staprans S, Loeb DD, Ganem D (1991) Mutations affecting hepadnavirus plus-strand DNA synthesis dissociate primer cleavage from translocation and reveal the origin of linear viral DNA. J Virol 65(3):1255–1262

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Lewellyn EB, Loeb DD (2007) Base pairing between cis-acting sequences contributes to template switching during plus-strand DNA synthesis in human hepatitis B virus. J Virol 81(12):6207–6215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Liu N, Tian R, Loeb DD (2003) Base pairing among three cis-acting sequences contributes to template switching during hepadnavirus reverse transcription. Proc Natl Acad Sci U S A 100(4):1984–1989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Tuttleman JS, Pourcel C, Summers J (1986) Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell 47(3):451–460

    Article  CAS  PubMed  Google Scholar 

  166. Wu TT, Coates L, Aldrich CE, Summers J, Mason WS (1990) In hepatocytes infected with duck hepatitis B virus, the template for viral RNA synthesis is amplified by an intracellular pathway. Virology 175(1):255–261

    Article  CAS  PubMed  Google Scholar 

  167. Block TM, Guo H, Guo JT (2007) Molecular virology of hepatitis B virus for clinicians. Clin Liver Dis 11(4):685–706, vii

    Article  PubMed  PubMed Central  Google Scholar 

  168. Bruss V, Ganem D (1991) The role of envelope proteins in hepatitis B virus assembly. Proc Natl Acad Sci U S A 88:1059–1063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Fernholz D, Stemler M, Brunetto M, Bonino F, Will H (1991) Replicating and virion secreting hepatitis B mutant virus unable to produce preS2 protein. J Hepatol 13:S102–S104

    Article  CAS  PubMed  Google Scholar 

  170. Jenna S, Sureau C (1998) Effect of mutations in the small envelope protein of hepatitis B virus on assembly and secretion of hepatitis delta virus. Virology 251:176–186

    Article  CAS  PubMed  Google Scholar 

  171. Tan WS, Dyson MR, Murray K (1999) Two distinct segments of the hepatitis B virus surface antigen contribute synergistically to its association with the viral core particles. J Mol Biol 286:797–808

    Article  CAS  PubMed  Google Scholar 

  172. Löffler-Mary H, Dumortier J, Klentsch-Zimmer C, Prange R (2000) Hepatitis B virus assembly is sensitive to changes in the cytosolic S loop of the envelope proteins. Virology 270:358–367

    Article  PubMed  CAS  Google Scholar 

  173. Wang J, Sheng Q, Ding Y, Chen R, Sun X, Chen X et al (2017) HBV RNA virion-like particles produced under nucleos(t)ide analogues treatment are mainly replication-deficient. J Hepatol. pii: S0168-8278(17)32413-3

    Google Scholar 

  174. Lam AM, Ren S, Espiritu C, Kelly M, Lau V, Zheng L et al (2017) Hepatitis B virus capsid assembly modulators, but not nucleoside analogs, inhibit the production of extracellular pregenomic RNA and spliced RNA variants. Antimicrob Agents Chemother 61(8):pii: e00680-17

    Article  Google Scholar 

  175. DiMattia MA, Watts NR, Stahl SJ, Grimes JM, Steven AC, Stuart DI et al (2013) Antigenic switching of hepatitis B virus by alternative dimerization of the capsid protein. Structure 21(1):133–142

    Article  CAS  PubMed  Google Scholar 

  176. Ning X, Luckenbaugh L, Liu K, Bruss V, Sureau C, Hu J (2018) Common and distinct capsid and surface protein requirements for secretion of complete and genome-free hepatitis B Virions. J Virol 92:pii: e00272-18

    Article  Google Scholar 

  177. Bardens A, Döring T, Stieler J, Prange R (2011) Alix regulates egress of hepatitis B virus naked capsid particles in an ESCRT-independent manner. Cell Microbiol 13:602–619

    Article  CAS  PubMed  Google Scholar 

  178. Döring T, Prange R (2015) Rab33B and its autophagic Atg5/12/16L1 effector assist in hepatitis B virus naked capsid formation and release. Cell Microbiol 17:747–764

    Article  PubMed  CAS  Google Scholar 

  179. Bai L, Zhang X, Kozlowski M, Li W, Wu M, Liu J et al (2018) Extracellular hepatitis B virus RNAs are heterogeneous in length and circulate as capsid-antibody complexes in addition to Virions in chronic hepatitis B patients. J Virol 27:92(24)

    Google Scholar 

  180. Summers J, O’Connell A, Millman I (1975) Genome of hepatitis B virus: restriction enzyme cleavage and structure of DNA extracted from Dane particles. Proc Natl Acad Sci U S A 72(11):4597–4601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Sureau C, Salisse J (2013) A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus a-determinant. Hepatology 57(3):985–994

    Article  CAS  PubMed  Google Scholar 

  182. Yang HC, Kao JH (2014) Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance. Emerg Microbes Infect 3(9):e64

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Zhang YY, Zhang BH, Theele D, Litwin S, Toll E, Summers J (2003) Single-cell analysis of covalently closed circular DNA copy numbers in a hepadnavirus-infected liver. Proc Natl Acad Sci U S A 100(21):12372–12377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Yang W, Summers J (1995) Illegitimate replication of linear hepadnavirus DNA through nonhomologous recombination. J Virol 69(7):4029–4036

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Bill CA, Summers J (2004) Genomic DNA double-strand breaks are targets for hepadnaviral DNA integration. Proc Natl Acad Sci U S A 101(30):11135–11140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Li X, Zhang J, Yang Z, Kang J, Jiang S, Zhang T et al (2014) The function of targeted host genes determines the oncogenicity of HBV integration in hepatocellular carcinoma. J Hepatol 60(5):975–984

    Article  PubMed  CAS  Google Scholar 

  187. Wang HP, Rogler CE (1991) Topoisomerase I-mediated integration of hepadnavirus DNA in vitro. J Virol 65(5):2381–2392

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Mason WS, Gill US, Litwin S, Zhou Y, Peri S, Pop O et al (2016) HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant. Gastroenterology 151(5):986–998

    Article  CAS  PubMed  Google Scholar 

  189. Rivkina MB, Lunin VG, Mahov AM, Tikchonenko TI, Kukain RA (1988) Nucleotide sequence of integrated hepatitis B virus DNA and human flanking regions in the genome of the PLC/PRF/5 cell line. Gene 64(2):285–296

    Article  CAS  PubMed  Google Scholar 

  190. Hu B, Wang R, Fu J, Su M, Du M, Liu Y et al (2018) Integration of hepatitis B virus S gene impacts on hepatitis B surface antigen levels in patients with antiviral therapy. J Gastroenterol Hepatol 33(7):1389–1396

    Article  CAS  PubMed  Google Scholar 

  191. Wooddell CI, Yuen MF, Chan HL, Gish RG, Locarnini SA, Chavez D et al (2017) RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med 9(409):pii: eaan0241

    Article  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by grants from the National S & T Major Project for Infectious Diseases (No. 2017ZX10302201) and the National Natural Science Foundation of China (No. 81672013).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fengmin Lu .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Wang, J. et al. (2020). HBV Genome and Life Cycle. In: Tang, H. (eds) Hepatitis B Virus Infection. Advances in Experimental Medicine and Biology, vol 1179. Springer, Singapore. https://doi.org/10.1007/978-981-13-9151-4_2

Download citation

Publish with us

Policies and ethics