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Chapter 8 : Hepatitis B Virus Replication, Liver Disease, and Hepatocellular Carcinoma

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Abstract:

One factor that has been of great importance to the study of hepatitis B virus (HBV) replication, and which will become of increasing importance in characterizing the biology of infection, is the existence of hepadnaviruses in other species. The two families of viruses infecting mammals and birds are subdivided into and , respectively. To appreciate the hepadnavirus replication scheme, it is important, first, to appreciate that hepadnaviruses have one of the smallest of all animal virus genomes. The viral envelope proteins are produced in greater abundance than required for virion production. Traditionally, the envelope gene and the corresponding regions of the envelope proteins are divided into preSl, preS2, and S domains. The hepadnaviruses all replicate via reverse transcription. However, despite some similarities to retrovirus replication, an important difference is that hepadnavirus replication does not involve formation of an integrated provirus. The potentially important but poorly understood issue in the biology of infections is the effect of hepatocyte proliferation on virus replication and on the evolution of liver disease. Constant stimulation of progenitor cell proliferation may be important in the disease process leading to hepatocellular carcinoma (HCC), tumors possibly arising from incompletely differentiated progenitor cells. The International Agency for Research on Cancer evaluated the evidence and concluded that "chronic infection with HBV is carcinogenic to humans" and classified HBV as a group 1 carcinogen. Therapy with a nucleoside analog inhibitor of virus replication appears likely, from preliminary results, to have the same limitation as interferon (IFN).

Citation: Mason W, Evans A, London W. 1998. Hepatitis B Virus Replication, Liver Disease, and Hepatocellular Carcinoma, p 253-281. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch8

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Figures

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Figure 1

The HBV genome. The placement of the various open reading frames and of the viral mRNAs relative to the relaxed circular virion DNA is shown. The RNAs are represented by solid lines on the outside of the diagram, and the coding regions are represented by lines with arrowheads. The short solid arrows indicate the start sites of the various viral RNAs. All end at a common polyadenylation site within the core gene.

Citation: Mason W, Evans A, London W. 1998. Hepatitis B Virus Replication, Liver Disease, and Hepatocellular Carcinoma, p 253-281. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch8
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Image of Figure 2
Figure 2

Hepadnavirus replication. The pathway for viral DNA synthesis is shown (see text and reference 116 for details). Virus, shown at the top left (A), may contain either circular or linear, partially double-stranded DNA. Following infection, viral DNA is delivered to the nucleus, where the DNA is completed and converted to a CCC form (B). The CCC DNA acts as the template for transcription of viral mRNAs, including a large terminally redundant RNA known as the pregenome (see Fig. 1). The pregenome has the capacity to act as mRNA for both the viral nucleocapsid (core protein) and the viral RT. Translation of the RT is infrequent, but when it occurs, this protein binds a stem-loop region at the 5′ end of the RNA known as epsilon (C) ( ). The complex is then assembled into viral nucleocapsids, where reverse transcription actually takes place. Initiation of minus-strand synthesis begins at a bulge in the stem-loop structure, from which four bases are copied, using a tyrosine-OH located in the N-terminal region of the RT as a primer ( ). The complex then translocates and base pairs to a homologous four-base sequence in the 3′-terminal redundancy of the pregenome, at a 10-to-12-base sequence known as DR1 (DR1 was so named because there is a copy of this sequence outside the terminal redundancy, about 50 to 200 bases upstream in different hepadnaviruses, denoted DR2). Reverse transcription then extends to the 5′ end of the minus strand as the pregenome is degraded by the viral RNase H. The capped 5′ end of the pregenome, 17 to 18 bases in length and extending through DR1, is retained and serves as the primer of second (plus)-strand synthesis ( ). Normally, priming occurs after a translocation event in which the primer is dissociated from DR1 and annealed to DR2 (D). The mechanism of translocation is unknown. Occasionally, stable translocation fails to occur and priming occurs at DR1 to produce linear viral genomes (E) ( ). Following extension to the 5′ end of the minus strand, plus-strand synthesis jumps to the 3′ end to create a circular DNA molecule. Circularization is apparently facilitated by the short (8 to 9 bases) terminal redundancy on the minus strand ( ). Plus-strand synthesis is never completed during virus assembly, and most virion DNA has a partially double-stranded, relaxed circular conformation, though some is linear. The RT, which served as the primer of reverse transcription, and the RNA, which primed plus-strand synthesis, remain attached to the DNA strands in mature virus.

Citation: Mason W, Evans A, London W. 1998. Hepatitis B Virus Replication, Liver Disease, and Hepatocellular Carcinoma, p 253-281. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch8
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Image of Figure 3
Figure 3

Prevalence of serum HBV DNA in HBV carriers from two different populations by age group. The presence of HBV DNA (virions) in serum was determined by standard filter DNA hybridization assays. The percent of carriers scoring positive in each age group, from 20 to 60 years, is shown. Further details are provided in the text.

Citation: Mason W, Evans A, London W. 1998. Hepatitis B Virus Replication, Liver Disease, and Hepatocellular Carcinoma, p 253-281. In McCance D (ed), Human Tumor Viruses. ASM Press, Washington, DC. doi: 10.1128/9781555818289.ch8
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References

/content/book/10.1128/9781555818289.chap8
1. Akarca, U. S.,, S. Greene,, and A. S. F. Lok. 1994. Detection of hepatitis B virus mutant in asymptomatic HBsAg-positive family members. Hepatology 19:13661370.
2. Akarca, U. S.,, and A. S. F. Lok. 1995. Naturally occurring hepatitis B virus core gene mutations. Hepatology 22:5060.
3. Beasley, R. P.,, and L.-Y. Hwang,. 1991. Overview on the epidemiology of hepatocellular carcinoma, p. 532535. In F. B. Hollinger,, S. M. Lemon,, and H. S. Margolis (ed.), Viral Hepatitis and Liver Disease. The Williams & Wilkins Co., Baltimore.
4. Beasley, R. P.,, C. Trepo,, C. E. Stevens,, and W. Szmuness. 1977. The e antigen and vertical transmission of hepatitis B surface antigen. Am. J. Epidemiol. 105:9498.
5. Berquist, K. R.,, J. M. Peterson,, B. L. Murphy,, J. W. Ebert,, J. E. Maynard,, and R. H. Purcell. 1973. Hepatitis B antigens in serum and liver of chimpanzees acutely infected with hepatitis B virus. J. Infect. Dis. 127:648652.
6. Blum, H. E.,, A. T. Haase,, and G. N. Vyas. 1984. Molecular pathogenesis of hepatitis B virus infection: simultaneous detection of viral DNA and antigens in paraffin-embedded liver sections. Lancet 2:771775.
7. Blumberg, B. S.,, B. J. S. Gerstley,, D. A. Hungerf ord,, W. T. London,, and A. I. Sutnik. 1967. A serum antigen (Australia antigen) inn Down's syndrome, leukemia and hepatitis. Ann. Intern. Med. 66:924931.
8. Brechot, C. 1987. Hepatitis B virus (HBV) and hepatocelular carcinoma. HBV status and its implication. J. Hepatol. 4:269.
9. Bressac, B.,, M. Kew,, J. Wands,, and M. Ozturk. 1991. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350:429431.
10. Bruss, V.,, and K. Vieluf. 1995. Functions of the internal pre-S domain of the large surface protein in hepatitis B virus particle morphogenesis. J. Virol. 69:66526657.
11. Buetow, K. FL, V. C. Sheffield, M. Zhu, T. Zhou, F. M. Shen, O. Hino, M. Smith, B. J. McMahon, A. P. Lanier, W. T. London, A. G. Redeker, and S. Govindarajan. 1992. Low frequency of p53 mutations observed in a diverse collection of primary hepatocellular carcinomas. Proc. Natl. Acad. Sci. USA 89:96229626.
12. Chisari, F. V. 1995. Hepatitis B virus immunopathogenesis. Annu. Rev. Immunol. 13: 2960.
13. Chisari, F. V.,, P. Filippi,, J. Buras,, A. McLachlan,, H. Popper,, C. A. Pinkert,, R. D. Palmiter,, and R. L. Brinster. 1987. Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. Proc. Natl. Acad. Sci. USA 84:69096913.
14. Chisari, F. V.,, K. Klopchin,, T. Moriyama,, C. Pasquinelli,, H. A. Dunsford,, S. Sell,, C. A. Pinkert,, R. L. Brinster,, and R. D. Palmiter. 1989. Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell 59:11451156.
15. Chu, C. M.,, Y. F. Liaw,, C. C. Pao,, and M. J. Huang. 1989. The etiology of acute hepatitis superimposed upon previously unrecognized asymptomatic HBsAg carriers. Hepatology 9:452456.
16. Civitico, G. M.,, and S. A. Locarnini. 1994. The half-life of duck hepatitis B virus supercoiled DNA in congenitally infected primary hepatocyte cultures. Virology 203: 8189.
17. Colombo, M.,, R. De Franchis,, E. Del Ninno,, A. Sangiovanni,, C. De Fazio,, M. Tommasini,, M. Donato,, A. Piva,, V. Di Carlo,, and N. Dioguardi. 1991. Hepatocellular carcinoma in Italian patients with cirrhosis. N. Engl. J. Med. 325:675680.
18. Concannon, P.,, P. Roberts,, B. Ball,, D. Schlafer,, X. Yang,, B. Baldwin,, and B. Tennant. 1997. Estrus, fertility, early embryo development and autologous embryo transfer in laboratory woodchucks (Marmota monax). Lab. Anim. Sci. 47:6374.
19. Condreay, L. D.,, C. E. Aldrich,, L. Coates,, W. S. Mason,, and T. T. Wu. 1990. Efficient duck hepatitis B virus production by an avian liver tumor cell line. J. Virol. 64: 32493258.
20. Cottone, M.,, M. Turri,, M. Caltagirone,, P. Parisi,, A. Orlando,, G. Fiorentino,, R. Virdone,, G. Fusco,, R. Grasso,, R. G. Simonetti,, and L. Pagliaro. 1994. Screening for hepatocellular carcinoma in patients with Child's A cirrhosis: an 8-year prospective study by ultrasound and alphafetoprotein. J. Hepatol. 21:10291034.
21. Dabeva, M. D.,, G. Alpini,, E. Hurston,, and D. A. Shafritz. 1993. Models for hepatic progenitor cell activation. Proc. Soc. Exp. Biol. Med. 204:242252.
22. Davis, G. L.,, J. H. Hoofnagle,, and J. G. Waggoner. 1984. Acute type A hepatitis during chronic hepatitis B virus infection: association of depressed hepatitis B virus replication with appearance of endogenous alpha interferon. J. Med. Virol. 14:141147.
23. deFranchis, R.,, G. Meucci,, M. Vecchi,, M. Tatarella,, M. Colombo,, N. E. Del,, M. G. Rumi,, M. F. Donato,, and G. Ronchi. 1993. The natural history of asymptomatic hepatitis B surface antigen carriers. Ann. Intern. Med. 118:191194.
24. Dejean, A.,, L. Bougueleret,, K. H. Grzeschik,, and P. Tiollais. 1986. Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature 322:7072.
25. D'Errico, A.,, W. F. Grigioni,, M. Fiorentino,, P. Baccarini,, E. Lamas,, M. S. De,, G. Gozzetti,, A. M. Mancini,, and C. Brechot. 1994. Expression of insulin-like growth factor II (IGF-II) in human hepatocellular carcinomas: an immunohistochemical study. Pathol. Int. 44:131137.
26. Dodd, R. Y.,, and N. Nath. 1987. Increased risk for lethal forms of liver disease among HBsAg-positive blood donors in the United States. J. Virol. Methods 17:8194.
27. Etiemble, J.,, C. Degott,, C. A. Renard,, G. Fourel,, B. Shamoon,, T. L. Vitvitski,, T. Y. Hsu,, P. Tiollais,, C. Babinet,, and M. A. Buendia. 1994. Liver-specific expression and high oncogenic efficiency of a c-myc transgene activated by woodchuck hepatitis virus insertion. Oncogene 9:727737.
28. Fausto, N. 1990. Hepatocyte differentiation and liver progenitor cells. Curr. Opin.Cell Biol. 2:10361042.
29. Fausto, N.,, J. M. Lemire,, and N. Shiojiri. 1993. Cell lineages in hepatic development and the identification of progenitor cells in normal and injured liver. Proc. Soc. Exp. Biol. Med. 214:237241.
30. Feitelson, M. A.,, and L.-X. Duan. 1997. Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. Am. J. Pathol. 150:11411157.
31. Feitelson, M. A.,, M. Zhu,, L. X. Duan,, and W. T. London. 1993. Hepatitis B x antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene 8:11091117.
32. Fourel, G.,, J. Couturier,, Y. Wei,, F. Apiou,, P. Tiollais,, and M. A. Buendia. 1994. Evidence for long-range oncogene activation by hepadnavirus insertion. EMBO J. 13:25262534.
33. Fourel, I.,, J. M. Cullen,, J. Saputelli,, C. E. Aldrich,, P. Schaffer,, D. Averett,, J. Pugh,, and W. S. Mason. 1994. Evidence that hepatocyte turnover is required for rapid clearance of DHBV during antiviral therapy of chronically infected ducks. J. Virol. 12:83218330.
34. Fu, X.-X.,, C. Y. Su,, Y. Lee,, R. Hintz,, L. Biempica,, R. Snyder,, and C. Rogler. 1988. Insulinlike growth factor II expression and oval cell proliferation associated with hepatocarcinogenesis in woodchuck hepatitis virus carriers. J. Virol. 62:34223430.
35. Fukao, A. 1985. An epidemiological study on relationship between hepatitis B virus and hepatocellular carcinoma. Jpn. J. Gastroenterol. 82:232238.
36. Ganem, D. 1991. Assembly of hepadnaviral virions and subviral particles. Curr. Top. Microbiol. Immunol. 168:6183.
37. Gerber, M. A.,, F. Schaffner,, and F. Paronetto. 1972. Immuno-electron microscopy of hepatitis B antigen in liver. 1. Proc. Soc. Exp. Biol. Med. 140:13341339.
38. Gish, R. G.,, J. Y. Lau,, L. Brooks,, J. W. Fang,, S. L. Steady,, J. C. Imperial,, K. R. Garcia,, C. O. Esquivel,, and E. B. Keeffe. 1996. Ganciclovir treatment of hepatitis B virus infection in liver transplant recipients. Hepatology 23:17.
39. Gong, S. S.,, A. D. Jensen,, and C. E. Rogler. 1996. Loss and acquisition of duck hepatitis B virus integrations in lineages of LMH-D2 chicken hepatoma cells. J. Virol. 70:20002007.
40. Gong, S. S.,, A. D. Jensen,, H. Wang,, and C. E. Rogler. 1995. Duck hepatitis B virus integrations in LMH chicken hepatoma cells: identification and characterization of new episomally derived integrations. J. Virol. 69:81028108.
41. Grisham, J. W. 1962. A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating rat liver; autoradiography with thymidine-H3. Cancer Res. 22:842849.
42. Grosovsky, A. J.,, J. G. DeBoer,, P. J. dejog,, E. A. Drobetsky,, and B. W. Glickman. 1988. Base substitutions, frame shifts, and small deletions constitute ionizing radiation induced point mutations in mammalian cells. Proc. Natl. Acad. Sci. USA 85: 185188.
43. Guidotti, L. G.,, P. Borrow,, M. V. Hobbs,, B. Matzke,, I. Gresser,, M. B. Oldstone,, and F. V. Chisari. 1996. Viral cross talk: intracellular inactivation of the hepatitis B virus during an unrelated viral infection of the liver. Proc. Natl. Acad. Sci. USA 93: 45894594.
44. Guidotti, L. G.,, T. Ishikawa,, M. V. Hobbs,, B. Matzke,, R. Schreiber,, and F. V. Chisari. 1996. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity 4:2536.
45. Guidotti, L. G.,, B. Matzke,, H. Schaller,, and F. V. Chisari. 1995. High-level hepatitis B virus replication in transgenic mice. J. Virol. 69:61586169.
46. Hadziyannis, S.,, E. Tabor,, E. Kaklamani,, A. Tzonou,, S. Stuver,, N. Tassopoulos,, N. Mueller,, and D. Trichopoulos. 1995. A case-control study of hepatitis B and C virus infections in the etiology of hepatocellular carcinoma. Int. J. Cancer 60:627631.
47. Hagen, T. M.,, S. Huang,, J. Curnutte,, P. Fowler,, V. Martinez,, C. M. Wehr,, B. N. Ames,, and F. C. Chisari. 1994. Extensive oxidative damage in hepatocytes of transgenic mice with chronic active hepatitis destined to develop chronic hepatitis. Proc. Natl. Acad. Sci. USA 91:1280812812.
48. Halpern, M. S.,, J. M. England,, D. T. Deery,, D. J. Petcu,, W. S. Mason,, and K. L. Molnar-Kimber. 1983. Viral nucleic acid synthesis and antigen accumulation in pancreas and kidney of Pekin ducks infected with duck hepatitis B virus. Proc. Natl. Acad. Sci. USA 80:48654869.
49. Hansen, L. J.,, B. C. Tennant,, C. Seeger,, and D. Ganem. 1993. Differential activation of myc gene family members in hepatic carcinogenesis by closely related hepatitis B viruses. Mol. Cell. Biol. 13:659667.
50. Heermann, K. H.,, U. Goldmann,, W. Schwartz,, T. Seyffarth,, H. Baumgarten,, and W. H. Gerlich. 1984. Large surface proteins of hepatitis B virus containing the pres sequence. J. Virol. 52:396402.
51. Henkler, F.,, N. Waseem,, M. H. Golding,, M. R. Alison,, and R. Koshy. 1995. Mutant p53 but not hepatitis B virus X protein is present in hepatitis B virus-related human hepatocellular carcinoma. Cancer Res. 55:60846091.
52. Hino, O.,, T. B. Shows,, and C. E. Rogler. 1986. Hepatitis B virus integration site in hepatocellular carcinoma at chromosome 17;18 translocation. Proc. Natl. Acad. Sci. USA 83:83388342.
53. Hohne, M.,, S. Schaefer,, M. Seifer,, M. A. Feitelson,, D. Paul,, and W. H. Gerlich. 1990. Malignant transformation of immortalized transgenic hepatocytes after trans-fection with hepatitis B virus DNA. EMBO J. 9:11371145.
54. Hoofnagle, J. H.,, and A. M. DiBisceglie. 1997. The treatment of chronic viral hepatitis. N. Engl. J. Med. 336:347356.
55. Hosono, S.,, M. J. Chou,, C. S. Lee,, and C. Shih. 1993. Infrequent mutation of p53 gene in hepatitis B virus positive primary hepatocellular carcinomas. Oncogene 8: 491496.
56. Hsia, C. C, D. J. Kleiner, C. A. Axiotis, B. A. Di, A. M. Nomura, G. N. Stemmermann, and E. Tabor. 1992. Mutations of p53 gene in hepatocellular carcinoma: roles of hepatitis B virus and aflatoxin contamination in the diet [see comments]. J. Natl. Cancer Inst. 84:16381641.
57.International Agency for Researchon Cancer. 1994. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans, vol. 59, Hepatitis Viruses. International Agency for Research on Cancer, Lyon, France.
58. Jansen, R. W.,, L. C. Johnson,, and D. R. Averett. 1993. High-capacity in vitro assessment of anti-hepatitis B virus compound selectivity by a virion-specific polymerase chain reaction assay. Antimicrob. Agents Chemother. 37:441447.
59. Jilbert, A. R.,, T.-T. Wu,, J. M. England,, P. de la M. Hall, N. Z. Carp, A. P. O'Connell, and W. S. Mason. 1992. Rapid resolution of duck hepatitis B virus infections occurs after massive hepatocellular involvement. J. Virol. 66:13771388.
60. Kajino, K.,, A. R. Jilbert,, J. Saputelli,, C. E. Aldrich,, J. Cullen,, and W. S. Mason.1994. Woodchuck hepatitis virus infections: very rapid recovery after a prolonged viremia and infection of virtually every hepatocyte. J. Virol. 68:57925803.
61. Kashala, L. O.,, B. Conne,, K. Y,, P. C. Frei,, P. H. Lambert,, M. R. Kalengayi,, and M. Essex. 1992. Hepatitis B virus, alpha-fetoprotein synthesis, and hepatocellular carcinoma in Zaire. Liver 12:330340.
62. Kawaguchi, T.,, K. Nomura,, Y. Hirayama,, and T. Kitagawa. 1987. Establishment and characterization of a chicken hepatocellular carcinoma cell line, LMH. Cancer Res. 47:44604464.
63. Kekule, A. S.,, U. Lauer,, M. Meyer,, W. H. Caselmann,, P. H. Hofschneider,, and R. Koshy. 1990. The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator. Nature 343:457461.
64. Korba, B. E.,, H. Xie,, K. N. Wright,, W. E. Hornbuckle,, J. L. Gerin,, B. C. Tennant,, and K. Y. Hostetler. 1996. Liver-targeted antiviral nucleosides: enhanced antiviral activity of phosphatidyl-dideoxyguanosine versus dideoxyguanosine in woodchuck hepatitis virus infection in vivo. Hepatology 23:958963.
65. Korba, B. E.,, F. V. Wells,, B. Baldwin,, P. J. Cote,, B. C. Tennant,, H. Popper,, and J. L. Gerin. 1989. Hepatocellular carcinoma in woodchuck hepatitis virus-infected woodchucks: presence of viral DNA in tumor tissue from chronic carriers and animals serologically recovered from acute infections. Hepatology 9:461470.
66. Korenman, J.,, B. Baker,, J. Waggoner,, J. E. Everhart,, A. M. Di Bisceglie,, and J. H. Hoofnagle. 1991. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann. Intern. Med. 114:629634.
67. Lauer, U.,, L. Weiss,, M. Lipp,, P. H. Hofschneider,, and A. S. Kekule. 1994. The hepatitis B virus preS2/St transactivator utilizes AP-1 and other transcription factors for transactivation. Hepatology 19:2331.
68. Lenhoff, R. J.,, and J. Summers. 1994. Construction of avian hepadnavirus variants with enhanced replication and cytopathicity in primary hepatocytes. J. Virol. 68: 57065713.
69. Lenhoff, R. J.,, and J. Summers. 1994. Coordinate regulation of replication and virus assembly by the large envelope protein of an avian hepadnavirus. J. Virol. 68: 45654571.
70. Lien, J. M.,, C. E. Aldrich,, and W. S. Mason. 1986. Evidence that a capped oligoribonucleotide is the primer for duck hepatitis B virus plus-strand DNA synthesis. J. Virol. 57:229236.
71. Lien, J. M.,, D. J. Petcu,, C. E. Aldrich,, and W. S. Mason. 1987. Initiation and termination of duck hepatitis B virus DNA synthesis during virus maturation. J. Virol. 61: 38323840.
72. Lin, T.-M.,, C.-J. Chen,, S.-N. Lu,, A.-S. Chang,, Y.-C. Chang,, S.-T. Hsu,, J.-Y. Liu,, Y.-F. Liaw,, and W.-Y. Chang. 1991. Hepatitis B virus e antigen and primary hepatocellular carcinoma. Anticancer Res. 11:20632066.
73. Ling, R.,, D. Mutimer,, M. Ahmed,, E. H. Boxall,, E. Elias,, G. M. Dusheiko,, and T. J. Harrison. 1996. Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine. Hepatology 24:711713.
74. Loeb, D. D.,, K. J. Gulya,, and R. Tian. 1997. Sequence identity of the terminal redundancies on the minus-strand DNA template is necessary but not sufficient for the template switch during hepadnavirus plus-strand DNA synthesis. J. Virol. 71: 152160.
75. Lok, A. S. 1991. Alpha-interferon therapy for chronic hepatitis B virus infection in children and Oriental patients. J. Gastroenterol. Hematol. 1:1517.
76. London, W.,, A. Evans,, K. McGlynn,, K. Buetow,, P. An,, E. Gao,, E. Ross,, G.-C. Chen,, and F.-M. Shen. 1995. Viral, host and environmental risk factors for hepatocellular carcinoma: a prospective study in Haimen City, China. Intervirology 38:155161.
77. Luber, B.,, N. Arnold,, M. Sturzl,, M. Hohne,, P. Schirmacher,, U. Lauer,, J. Wienberg,, P. H. Hofschneider,, and A. S. Kekule. 1996. Hepatoma-derived integrated HBV DNA causes multi-stage transformation in vitro. Oncogene 12:15971608.
78.Luscombe, C, J. Pedersen, E. Uren, and S. Locarnini. 1996. Long-term ganciclovir chemotherapy for congenital duck hepatitis B virus infection in vivo: effect on intra-hepatic-viral DNA, RNA, and protein expression. Hepatology 24:766773.
79. MacDonald, R. A. 1960. "Lifespan" of liver cells. Arch. Intern. Med. 107:335343.
80. Mancini, M.,, H. Davis,, P. Tiollais,, and M. L. Michel. 1996. DNA-based immunization against the envelope proteins of the hepatitis B virus. J. Biotechnol. 44:4757.
81. Marinier, E.,, V. Barrois,, B. Larouze,, W. T. London,, A. Cofer,, L. Diakhate,, and B. S. Blumberg. 1985. Lack of perinatal transmission of hepatitis B virus infection in Senegal, West Africa. J. Pediatr. 106:843849.
82. Marion, P. L.,, J. M. Cullen,, R. R. Azcarrraga,, D. M. Van,, and W. S. Robinson. 1987. Experimental transmission of duck hepatitis B virus to Pekin ducks and to domestic geese. Hepatology 1987:724731.
83. Marion, P. L.,, L. S. Oshiro,, D. C. Regnery,, G. H. Scullard,, and W. S. Robinson. 1980. A virus in Beechey ground squirrels which is related to hepatitis B virus of man. Proc. Natl. Acad. Sci. USA 77:29412945.
84. Marion, P. L.,, H. Popper,, R. R. Azcarraga,, C. Steevens,, M. J. V. Davelaar,, G. Garcia,, and W. S. Robinson,. 1987. Ground squirrel hepatitis virus and hepatocellular carcinoma, p. 337348. In W. Robinson,, K. Koike,, and H. Will (ed.), Hepadnaviruses. A. R. Liss, Inc., New York.
85. Marion, P. L.,, M. J. Van Davelaar,, S. S. Knight,, F. H. Salazar,, G. Garcia,, H. Popper,, and W. S. Robinson. 1986. Hepatocellular carcinoma in ground squirrels persistently infected with ground squirrel hepatitis virus. Proc. Natl. Acad. Sci. USA 83:45434546.
86. Mason, W. S.,, G. Seal,, and J. Summers. 1980. Virus of Pekin ducks with structural and biological relatedness to human hepatitis B virus. J. Virol. 36:829836.
87. McBride, T. J.,, B. D. Preston,, and L. A. Loeb. 1991. Mutagenic spectrum resulting from DNA damage by oxygen radicals. Biochemistry 30:207213.
88. McGlynn, K. A.,, E. A. Rosvold,, E. D. Lustbader,, Y. Hu,, M. Clapper,, T. Zhou,, C. P. Wild,, X.-L. Xia,, A. Baffoe-Bonnie,, D. Ofori-Adjei,, G.-C. Chen,, W. T. London,, F.-M. Shen,, and K. H. Buetow. 1995. Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin Bl. Proc. Natl. Acad. Sci. USA 92:23842387.
89. McMahon, B.,, S. Alberts,, R. Wainwright,, L. Bulkow,, and A. Lanier. 1990. Hepatitis B-related sequelae: prospective study in 1400 hepatitis B surface antigen-positive Alaska Native carriers. Arch. Intern. Med. 150:10511054.
90. Milich, D. R.,, J. E. Jones,, J. L. Hughes,, J. Price,, A. K. Raney,, and A. McLachlan. 1990. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc. Natl. Acad. Sci. USA 87:65996603.
91. Nagaya, T.,, T. Nakamura,, T. Tokino,, T. Tsurimoto,, M. Imai,, T. Mayumi,, K. Kamino,, K. Yamamura,, and K. Matsubara. 1987. The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma. Genes Dev. 1:773782.
92. Negro, F.,, B. E. Korba,, B. Forzani,, B. M. Baroudy,, T. L. Brown,, J. L. Gerin,, and A. Ponzetto. 1989. Hepatitis delta virus (HDV) and woodchuck hepatitis virus (WHV) nucleic acids in tissues of HDV-infected chronic WHV carrier woodchucks. J. Virol. 63:16121618.
93. Newbold, J. E.,, H. Xin,, M. Tencza,, G. Sherman,, J. Dean,, S. Bowden,, and S. Locarnini. 1995. The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minichromosomes. J. Virol. 69:33503357.
94.Niederau, C, T. Heintges, S. Lange, G. Goldmann, C. M. Niederau, L. Mohr, D. Haussinger. 1996. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N. Engl. J. Med. 334:14221427.
95. Norder, H.,, J. W. Ebert,, H. A. Fields,, I. K. Mushahwar,, and L. O. Magnius. 1996. Complete sequencing of a gibbon hepatitis B virus genome reveals a unique genotype distantly related to the chimpanzee hepatitis B virus. Virology 218:214223.
96. Nowak, M. A.,, S. Bonhoeffer,, A. M. Hill,, R. Boehme,, H. C. Thomas,, and H. McDade. 1996. Viral dynamics in hepatitis B virus infection. Proc. Natl. Acad. Sci. USA 93:43984402.
97. Obert, S.,, B. B. Zachmann,, E. Deindl,, W. Tucker,, R. Bartenschlager,, and H. Schaller. 1996. A splice hepadnavirus RNA that is essential for virus replication. EMBO J. 15: 25652574.
98. O'Connell, A. P.,, M. K. Urban,, and W. T. London. 1983. Naturally occurring infection of Pekin duck embryos by duck hepatitis B virus. Proc. Natl. Acad. Sci. USA 80: 17031706.
99. Ogston, C. W.,, G. J. Jonak,, C. E. Rogler,, S. M. Astrin,, and J. Summers. 1982. Cloning and structural analysis of integrated woodchuck hepatitis virus sequences from hepatocellular carcinomas of woodchucks. Cell 29:385394.
100. Oshima, A.,, H. Tsukuma,, T. Hiyama,, I. Fujimoto,, H. Yamano,, and M. Tanaka. 1984. Follow-up study of HBs Ag-positive blood donors with special reference to effect of drinking and smoking on development of liver cancer. Int. J. Cancer 34: 775779.
101. Ou, J. H.,, O. Laub,, and W. J. Rutter. 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. USA 83:15781582.
102. Perrillo, R. P.,, E. R. Schiff,, G. L. Davis,, H. C. Bodenheimer,, K. Lindsay,, J. Payne,, J. L. Dienstag,, C. O'Brein,, C. Tamburro,, I. M. Jacobson,, R. Sampliner,, D. Feit,, J. Lefkowitch,, M. Kuhns,, C. Meschievitz,, B. Sanghvi,, J. Albrecht,, and A. Gibas. 1990. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. N. Engl. J. Med. 323:295301.
103. Ponzetto, A.,, P. J. Cote,, E. C. Ford,, R. H. Purcell,, and J. L. Gerin. 1984. Core antigen and antibody in woodchucks after infection with woodchuck hepatitis virus. J. Virol. 52:7076.
104. Popper, H.,, L. Roth,, R. H. Purcell,, B. C. Tennant,, and J. L. Gerin. 1987. Hepatocarcinogenicity of the woodchuck hepatitis virus. Proc. Natl. Acad. Sci. USA 84:866870.
105. Prince, A. M.,, and P. Alcabes. 1982. The risk of development of hepatocellular carcinoma in hepatitis B virus carriers in New York. A preliminary estimate using death-records matching. Hepatology 2:15S20S.
106. Prince, M. A.,, T. White,, N. Pollock,, J. Riddle,, B. Brotman,, and L. Richardson. 1981. Epidemiology of hepatitis B infection in Liberian infants. Infect. Immun. 32:675.
107. Pugh, J.,, A. Zweidler,, and J. Summers. 1989. Characterization of the major duck hepatitis B virus core particle protein. J. Virol. 63:13711376.
108. Quignon, F.,, C. A. Renard,, P. Tiollais,, M. A. Buendia,, and C. Transy. 1996. A functional N-myc2 retroposon in ground squirrels: implications for hepadnavirus-associated carcinogenesis. Oncogene 12:20112017.
109. Rivkina, M. B.,, J. M. Cullen,, W. S. Robinson,, and P. L. Marion. 1994. State of the p53 gene in hepatocellular carcinomas of ground squirrels and woodchucks with past and ongoing infection with hepadnaviruses. Cancer Res. 54:54305437.
110. Ryder, R. W.,, H. C. Whittle,, A. B. Sanneh,, A. B. Ajdukiewicz,, S. Tulloch,, and B. Yvonnet. 1992. Persistent hepatitis B virus infection and hepatoma in The Gambia, west Africa. A case-control study of 140 adults and their 603 family contacts. Am. J. Epidemiol. 136:11221131.
111. Sakuma, K.,, N. Saitoh,, M. Kasai,, H. Jitsukawa,, L. Yoshino,, M. Yamaguchi,, K. Nobutomo,, M. Yamumi,, F. Tsuda,, T. Komazawa,, T. Nakamura,, Y. Yoshida,, and K. Okuka. 1988. Relative risks of death due to liver disease among Japanese male adults having various statuses for hepatitis B s and c antigen/antibody in serum: a prospective study. Hepatology 8:16421646.
112. Schaller, H.,, and M. Fischer. 1991. Transcriptional control of hepadnavirus gene expression. Curr. Top. Microbiol. Immunol. 168:2139.
113. Scorsone, K. A.,, Y. Z. Zhou,, J. S. Butel,, and B. L. Slagle. 1992. p53 mutations cluster at codon 249 in hepatitis B virus-positive hepatocellular carcinomas from China. Cancer Res. 52:16351638.
114.Seeger, C, B. Baldwin, W. E. Hornbuckle, A. E. Yeager, B. C. Tennant, P. Cote, L. Ferrell, D. Ganem, and H. E. Varmus. 1991. Woodchuck hepatitis virus is a more efficient oncogenic agent than ground squirrel hepatitis virus in a common host. J. Virol. 65:16731679.
115.Seeger, C, D. Ganem, and H. E. Varmus. 1986. Biochemical and genetic evidence for the hepatitis B virus replication strategy. Science 232:477484.
116. Seeger, C.,, and W. S. Mason,. 1996. Reverse transcription and amplification of the hepatitis B virus genome, p. 815831. In M. DePamphilis (ed.), DNA Replication in Eukaryotic Cells. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.
117. Seeger, C.,, and W. S. Mason,. Chronic hepadnavirus infections of the woodchuck and duck. In R. Ahmed, and I. Chen (ed.), Persistent Viral Infections, John Wiley & Sons, New York, in press.
118. Shaw, T.,, S. S. Mok,, and S. A. Locarnini. 1996. Inhibition of hepatitis B virus DNA polymerase by enantiomers of penciclovir triphosphate and metabolic basis for selective inhibition of HBV replication by penciclovir. Hepatology 24:9961002.
119. Sheen, I. S.,, Y. F. Liaw,, D. I. Tai, et al. 1985. Hepatic decompensation associated with hepatitis B e antigen clearance in chronic type B hepatitis. Gastroenterology 89: 732735.
120. Sherman, M.,, K. M. Peltekian,, and C. Lee. 1995. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population. Hepatology 22:432438.
121.Shih, C, K. Burke, M. J. Chou, J. B. Zeldis, C. S. Yang, C. S. Lee, K. J. Isselbacher, J. R. Wands, and H. M. Goodman. 1987. Tight clustering of human hepatitis B virus integration sites in hepatomas near a triple-stranded region. J. Virol. 61:34913498.
122. Shimoda, R.,, M. Nagashima,, M. Sakamoto,, N. Yamaguchi,, S. Hirohashi,, J. Yokota,, and H. Kasai. 1994. Increased formation of oxidative DNA damage, 8-hydrodeoxygu-anosine, in human livers with chronic hepatitis. Cancer Res. 54:31713172.
123. Sirica, A. E. (ed.). 1992. The Role of Cell Types in Hepatocarcinogenesis. CRC Press, Boca Raton, Fla.
124. Sprengel, R.,, E. F. Kaleta,, and H. Will. 1988. Isolation and characterization of a hepatitis B virus endemic in herons. J. Virol. 62:932937.
125. Staprans, S.,, D. D. Loeb,, and D. Ganem. 1991. Mutations affecting hepadnavirus plus-strand DNA synthesis dissociate primer cleavage from translocation and reveal the origin of linear viral DNA. J. Virol. 65:12551262.
126. Stevens, C. E.,, R. A. Neurath,, R. P. Beasley,, and W. Szmuness. 1979. HBeAg and anti-HBe detection by radioimmunoassay: correlation with vertical transmission of hepatitis B virus in Taiwan. J. Med. Virol. 3:237241.
127. Summers, J.,, P. M. Smith,, and A. L. Horwich. 1990. Hepadnavirus envelope proteins regulate covalently closed circular DNA amplification. J. Virol. 64:28192824.
128. Summers, J.,, P. M. Smith,, M. J. Huang,, and M. S. Yu. 1991. Morphogenetic and regulatory effects of mutations in the envelope proteins of an avian hepadnavirus. J. Virol. 65:13101317.
129. Summers, J.,, J. Smolec,, and R. Snyder. 1978. A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proc. Natl. Acad. Sci. USA 75:45334537.
130. Szmuness, W.,, C. E. Stevens,, H. Ikram,, M. I. Much,, E. J. Harley,, and B. Hollinger. 1978. Prevalence of hepatitis B virus infection and hepatocellular carcinoma in Chinese-Americans. J. Infect. Dis. 137:822829.
131. Tagawa, M.,, W. S. Robinson,, and P. L. Marion. 1987. Duck hepatitis B virus replicates in the yolk sac of developing embryos. J. Virol. 61:22732279.
132. Takayanagi, M.,, S. Kkakumu,, T. Ishikawa,, Y. Higashi,, K. Yoshioka,, and T. Wakita. 1993. Comparison of envelope and precore/core variants of hepatitis B virus (HBV) during chronic HBV infection. Virology 196:138145.
133. Tennant, B. C, N. Mrosovsky, K. McLean, P. J. Cote, B. E. Korba, R. E. Engle, J. L. Gerin, J. Wright, G. R. Michener, E. Uhl, and J. M. King. 1991. Hepatocellular carcinoma in Richardson's ground squirrels (Spermophilus richardsonii): evidence for association with hepatitis B-like virus infection. Hepatology 13:12151221.
134. Testut, P.,, C. A. Renard,, O. Terradillos,, T. L. Vitvitski,, F. Tekaia,, C. Degott,, J. Blake,, B. Boyer,, and M. A. Buendia. 1996. A new hepadnavirus endemic in arctic ground squirrels in Alaska. J. Virol. 70:42104219.
135. Thorgeirsson, S. S.,, R. P. Evarts,, H. C. Bisgaard,, K. Fujio,, and Z. Hu. 1993. Hepatic stem cell compartment: activation and lineage commitment. Proc. Soc. Exp. Biol. Med. 204:253260.
136. Tipples, G. A.,, M. M. Ma,, K. P. Fischer,, V. G. Bain,, N. M. Kneteman,, and D. L. J. Tyrrell. 1996. Mutation in HBV DNA-dependent DNA polymerase confers resistance to lamivudine in vivo. Hepatology 24:714717.
137. Tokudome, S.,, M. Ikeda,, K. Matsushita,, Y. Maeda,, and M. Yoshinara. 1987. Hepatocellular carcinoma among female Japanese hepatitis B virus carriers. Hepato-Gastroen-terology 34:246248.
138.Transy, C, G. Fourel, W. S. Robinson, P. Tiollais, P. L. Marion, and M. A. Buendia. 1992. Frequent amplification of c-myc in ground squirrel liver tumors associated with past or ongoing infection with a hepadnavirus. Proc. Natl. Acad. Sci. USA 89: 38743878.
139.Transy, C, C. A. Renard, and M. A. Buendia. 1994. Analysis of integrated ground squirrel hepatitis virus and flanking host DNA in two hepatocellular carcinomas. J. Virol. 68:52915295.
140. Trueba, D.,, M. Phelan,, J. Nelson,, F. Beck,, B. S. Pecha,, R. J. Brown,, H. E. Varmus,, and D. Ganem. 1985. Transmission of ground squirrel hepatitis virus to homologous and heterologous hosts. Hepatology 5:435439.
141. Tsui, L. V.,, L. G. Guidotti,, T. Ishikawa,, and F. V. Chisari. 1995. Posttranscriptional clearance of hepatitis B virus RNA by cytotoxic T lymphocyte-activated hepatocytes. Proc. Natl. Acad. Sci. USA 92:1239812402.
142. Tu, J. T.,, R. N. Gao,, D. H. Zhang,, and B. C. Gu. 1985. Hepatitis B virus and primary liver cancer on Chongming Island, People's Republic of China. Natl. Cancer Inst. Monogr. 69:213215.
143. Tuttleman, J.,, C. Pourcel,, and J. Summers. 1986. Formation of the pool of covalently closed circular viral DNA in hepadnavirus infected cells. Cell 47:451460.
144. Ueda, K.,, and D. Ganem. 1996. Apoptosis is induced by N-myc expression in hepatocytes, a frequent event in hepadnavirus oncogenesis, and is blocked by insulin-like growth factor II. J. Virol. 70:13751383.
145. Ueda, K.,, Y. Wei,, and D. Ganem. 1996. Activation of N-myc2 gene expression by cis-acting elements of oncogenic hepadnaviral genomes: key role of enhancer II. Virology 217:413417.
146. Urban, M. K.,, A. P. O'Connell,, and W. T. London. 1985. Sequence of events in natural infection of Pekin duck embryos with duck hepatitis B virus. J. Virol. 55: 1622.
147. Vierucci, A.,, M. deMarino,, E. Graziani,, M. E. Rossi,, W. T. London,, and B. S. Blum-berg. 1983. A mechanism for liver cell injury in viral hepatitis: effects of hepatitis B virus on neutrophil function in vitro and in children with chronic hepatitis. Pediatr. Res. 17:814820.
148. Villeneuve, J. P.,, M. Desrochers,, R. C. Infante,, B. Willems,, G. Raymond,, M. Bour-cier,, J. Cote,, and G. Richer. 1994. A long-term follow-up study of asymptomatic hepatitis B surface antigen-positive carriers in Montreal. Gastroenterology 106: 10001005.
149. Wang, G. H.,, and C. Seeger. 1993. Novel mechanism for reverse transcription in hepatitis B viruses. J. Virol. 67:65076512.
150. Wang, G. H.,, F. Zoulim,, E. H. Leber,, J. Kitson,, and C. Seeger. 1994. Role of RNA in enzymatic activity of the reverse transcriptase of hepatitis B viruses. J. Virol. 68: 84378442.
151. Wang, J.,, X. Chenivesse,, B. Henglein,, and C. Brechot. 1990. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343:555557.
152. Wang, X. W.,, K. Forrester,, H. Yeh,, M. A. Feitelson,, J. R. Gu,, and C. C. Harris. 1994. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc. Natl. Acad. Sci. USA 91:22302234.
153. Wang, X. W.,, M. K. Gibson,, W. Vermeulen,, H. Yeh,, K. Forrester,, H. W. Sturzbecher,, J. H. Hoeijmakers,, and C. C. Harris. 1995. Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Cancer Res. 55:60126016.
154. Wei, Y.,, J. Etiemble,, G. Fourel,, T. L. Vitvitski,, and M. A. Buendia. 1995. Hepadna virus integration generates virus-cell cotranscripts carrying 3' truncated X genes in human and woodchuck liver tumors. J. Med. Virol. 45:8290.
155. Wei, Y.,, G. Fourel,, A. Ponzetto,, M. Silvestro,, P. Tiollais,, and M.-A. Buendia. 1992. Hepadnavirus integration: mechanisms of activation of the N-myc2 retrotransposon in woodchuck liver tumors. J. Virol. 66:52655276.
156. Wei, Y.,, and D. Ganem. 1996. Relationship between viral DNA synthesis and virion envelopment in hepatitis B viruses. J. Virol. 70:64556458.
157. Wei, Y.,, A. Ponzetto,, P. Tiollais,, and M. A. Buendia. 1992. Multiple rearrangements and activated expression of c-myc induced by woodchuck hepatitis virus integration in a primary liver tumour. Res. Virol. 143:8996.
158. Will, H.,, W. Reiser,, T. Weimer,, E. Pfaff,, M. Buscher,, R. Sprengel,, R. Cattaneo,, and H. Schaller. 1987. Replication strategy of human hepatitis B virus. J. Virol. 61:904911.
159. Yaginuma, K.,, H. Kobayashi,, M. Kobayashi,, T. Morishima,, K. Matsuyama,, and K. Koike. 1987. Multiple integration site of hepatitis B virus DNA in hepatocellular carcinoma and chronic active hepatitis tissues from children. J. Virol. 61:18081813.
160. Yang, D.,, E. Alt,, and C. E. Rogler. 1993. Coordinate expression of N-myc 2 and insulin-like growth factor II in precancerous altered hepatic foci in woodchuck hepatitis virus carriers. Cancer Res. 53:20202027.
161. Yang, D.,, R. Faris,, D. Hixson,, S. Affigne,, and C. E. Rogler. 1996. Insulin-like growth factor II blocks apoptosis of N-myc2-expressing woodchuck liver epithelial cells. J. Virol. 70:62606268.
162. Yang, W.,, W. S. Mason,, and J. Summers. 1996. Covalently closed circular viral DNA formed from two types of linear DNA in woodchuck hepatitis virus-infected liver. J. Virol. 70:45674575.
163. Yang, W.,, and J. Summers. 1995. Illegitimate replication of linear hepadnavirus DNA through nonhomologous recombination. J. Virol. 69:40294036.
164. Zhihong, J.,, Z. Guolong,, X. Shisong,, K. Pingyuan,, M. Lili,, C. Hongtao,, Q. Jianying,, B. Quiju,, and M. Kai. 1988. An experimental transmission of woodchuck hepatitis virus to young Chinese marmots. Hepatology 8:371373.
165. Zoulim, F.,, J. Saputelli,, and C. Seeger. 1994. Woodchuck hepatitis virus X protein is required for viral infection in vivo. J. Virol. 68:20262030.
166. Zoulim, F.,, and C. Seeger. 1994. Reverse transcription in hepatitis B viruses is primed by a tyrosine residue of the polymerase. J. Virol. 68:613.

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