Book on hepatitis from page 75 to 85

Book on hepatitis from page 75 to 85

HBV Virology  75
by capsid-assisted reverse transcription may result from a non-identical supply of
dNTPs inside individual nucleocapsids at the moment of their enclosure by the
dNTP impermeable envelope. This predicts that intracellular cores produced in the
absence of envelopment should contain further extended positive DNAs.
Alternatively, space restrictions in the capsid lumen could prevent plus-strand DNA
completion; in this view, further plus-strand elongation after infection of a new cell
might destabilize the nucleocapsid and thus be involved in genome uncoating (Beck
2007, Nassal 2008)
The final replication step, the assembly and release of HBV Dane particles, is also
not fully understood. The envelopment of the DNA-containing nucleocapsids
requires a balanced coexpression of the S and L proteins in order to recruit the
nucleocapsid to the site of budding. Although the role of the envelope proteins in
regulating the amplification of cccDNA in HBV is not well-characterised, recent
studies indicate that the lack of expression of the envelope proteins increased
cccDNA levels, while coexpression of the envelope proteins not only favours the
secretion of viral particles, but also limits the completion of the plus-strand (Lentz
2011).
Animal models of HBV infection
Because of the narrow host range and the lack of easily accessible and robust in
vitro infection systems the study of HBV biology has been limited. Consequently it
has been attempted by researchers all over the world to establish animal models and
cell culture systems that at least partially reproduce some stages of HBV infection
and can be used, e.g., for the preclinical testing of novel antiviral drugs.
Most of the progress in hepatitis B virus research are based on infection studies
performed with the two most used HBV-related animal viruses: DHBV, which
infects Peking ducks (Mason 1980) and WHV (Summers 1978), which infects the
Eastern American woodchuck (Marmota monax).
One of the major advantages of the DHBV model is that domestic Peking ducks
can be used under normal laboratory conditions and DHBV-permissive primary
hepatocytes from ducklings or embryos are easily accessible. Furthermore, ducks
show very high infectivity rates in vivo (Jilbert 1996) with high levels of DHBV
replication and antigen expression. However, in contrast to mammalian
hepadnaviruses, DHBV infection is cleared within a few days post-infection if the
virus is not transmitted vertically. The DHBV genome is also smaller than that of
the mammalian hepadnaviruses and  shares little primary nucleotide sequence
homology (40%) with HBV. Furthermore, DHBV infection is usually not associated
with liver disease and development of hepatocellular carcinoma (HCC).
Nevertheless, the duck model was widely used in preclinical trials (Zimmerman
2008, Reaiche 2010, Chayama 2011) and has contributed substantially to elucidate
the hepadnaviral replication scheme (Mason 1982, Summers 1988, Delmas 2002).
In vitro and in vivo studies with woodchuck hepatitis B virus (WHV) have been
fundamental in the preclinical evaluation of antiviral drugs now in use for treatment
of HBV infection (Moraleda 1997, Tennant 1998, Mason 1998, Block 1998, Dandri
2000, Korba 2004, Menne 2005). This is due to the fact that WHV is more similar
to HBV in terms of genomic organization than the avian hepadnaviruses.
Experimental infection of newborn woodchucks almost invariably leads to chronic
76  Hepatology 2012
infection, whereas most animals infected at older ages develop acute hepatitis that
results in an efficient immune response leading to viral clearance. Since acute and
chronic WHV infections in woodchucks show serological profiles similar to those
of HBV infection in humans, the woodchuck system has provided important
information about factors involved in the establishment of  virus infection,
replication and viral persistence (Lu 2001). Virtually all WHV chronic carrier
woodchucks succumb to HCC 2-4 years post infection. Like in human HCC,
regenerative hepatocellular nodules and hepatocellular adenomas are
characteristically observed in WHV-infected woodchuck livers (Korba 2004).
Proto-oncogene activation by WHV DNA integration has been observed frequently
and is thought to play an important role in driving hepatocarcinogenesis in
woodchucks, often activating a member of the myc family by various mechanisms
(Tennant 2004). Viral integration is commonly found in woodchucks even after
resolution of transient infection with WHV (Summers 2003), while its frequency
increases dramatically in chronically infected animals (Mason 2005). Interestingly,
WHV viral integration was used as a genetic marker to follow the fate of infected
hepatocytes during resolution of transient infection in woodchucks (Summers 2003)
and to estimate the amount of cell turnover occurring in the course of chronic
infection (Mason 2005).  Experimental infection studies in woodchucks also
demonstrated that WHV mutants that lacked the X gene were unable or severely
impaired to replicate  in vivo  (Chen 1993, Zoulim 1994, Zhang 2001). The
woodchuck model of viral-induced HCC has been used to test chemoprevention of
HCC using long-term antiviral nucleoside therapy and for the development of new
imaging agents for the detection of hepatic neoplasms by ultrasound and magnetic
resonance imaging (Tennant 2004). One main difference between human and rodent
hepatitis B resides in the absence of associated cirrhosis in woodchuck and squirrel
livers, even after prolonged viral infection (Buendia 1998). It is possible that the
rapid onset of hepatocyte proliferation following liver damage in rodents does
account for this discrepancy. In general, despite important advances achieved in
understanding the pathogenesis of WHV infection, one general disadvantage for
using woodchucks is that they are genetically heterogeneous animals, difficult to
breed in captivity and to handle in a laboratory setting.
Although HBV infects humans exclusively, it can be used to infect chimpanzees
experimentally and, to a certain extent, tupaia, the Asian tree shrew (Baumert
2005). Chimpanzees were the first animals found to be susceptible to HBV infection
(Barker 1973) and play an important role in the development of vaccines and in the
evaluation of the efficacy of therapeutic antibodies (Ogata 1999, Dagan 2003).
Though chimpanzees are not prone to develop  chronic liver disease (Gagneux
2004), they provide an ideal model for the analysis of early immunological events
of HBV acute infection and pathogenesis (Guidotti 1999). Infection experiments
with chimpanzees showed that the majority of viral DNA is eliminated from the
liver by non-cytolytic mechanisms that precedes the peek of T cell infiltration
(Guidotti 1999). T cell depletion studies in chimpanzees also indicate that the
absence of CD8-positive cells greatly delay the onset of viral clearance (Thimme
2003). Chimpanzees have been used for preclinical testing of preventive and
therapeutic vaccines (Will 1982, Guidotti 1999, Iwarson 1985, Kim 2008, Murray
2005). Nonetheless, the large size, the strong ethical constraints and the high costs
of chimpanzees severely limit their use for research purposes. 
HBV Virology  77
The tree shrew species Tupaia belangeri has been analyzed for the study of HBV
infection both in vitro and in vivo, taking advantage of the adaptability of these non-rodent mammals to the laboratory environment (Baumert 2005, von Weizsacker
2004). Inoculation of tree shrews with HBV-positive human serum was shown to
result in viral DNA replication in their livers, HBsAg secretion into the serum, and
production of antibodies to HBsAg and HBeAg (Walter 1996). Although
experimental infection of tree shrew with HBV infectious serum is not highly
efficient, productive HBV infection was successfully passed through five generations
of tree shrews and was specifically blocked by immunization with hepatitis B vaccine
(Yan 1996a). Interestingly, the development of hepatocellular carcinoma in tree
shrews exposed to hepatitis B virus and/or aflatoxin B1 was reported (Yan 1996b).
Whereas experimental infection of tree shrews causes only a mild, transient infection
with low viral titers in these animals, primary hepatocytes isolated from T. belangeri
turned out to be a valuable alternative source of HBV-permissive cells (von
Weizsacker 2004). More recently, the woolly monkey hepatitis B virus (WMHV)
was isolated from a woolly monkey (Lagothrix lagotricha), an endangered new world
primate (Lanford 1998). Interestingly, it has been shown that primary tupaia
hepatocytes are susceptible to infection with WMHBV (Kock 2001, Dandri 2005a),
providing a useful and more accessible alternative system for studying the early steps
of hepadnaviral infection in vitro (Schulze 2011) and in vivo (Petersen 2008).
Because of the different limitations encountered using chimpanzees and models
based on HBV-related viruses, it is not surprising that recent developments have
focused on using the natural target of HBV infection: the human hepatocyte.
However, primary human hepatocytes are not easy to handle, cannot be propagated
in vitro and their susceptibility to HBV infection is generally low and highly
variable. Furthermore, cultured cells may respond differently to the infection than
hepatocytes in the liver. The generation of mice harboring human chimeric livers
offered new possibilities to overcome some of these limitations. Two major models
are currently available: the urokinase-type plasminogen activator (uPA) transgenic
mouse (Rhim 1994) and the knockout fumarylacetoacetate hydrolase (FAH) mouse
(Azuma 2007). In both systems, the absence of adaptive immune responses permits
the engraftment of transplanted xenogenic hepatocytes, while the presence of
transgene-induced hepatocyte damage creates the space and the regenerative
stimulus necessary for the transplanted cells to repopulate the mouse liver. Both
models permit the establishment of HBV infection, which can then persist for the
life-span of the chimeric mouse (Dandri 2001, Bissig 2010).  While mouse
hepatocytes do not support HBV infection, human chimeric mice can be efficiently
infected by injecting infectious serum derived from either patients or chimeric mice.
Furthermore, genetically engineered viruses created in cell culture can be used to
investigate phenotype and in vivo fitness of distinct HBV genotypes and variants
(Tsuge 2005). Within the mouse liver human hepatocytes maintain a functional
innate immune system and respond to stimuli induced by exogenously applied
human IFN α.  The lack of an adaptive immune system and the undetectable
responsiveness of mouse liver cells to human IFN α make the model ideal to exploit
the capacities of HBV to interfere with pathways of the innate antiviral response in
human hepatocytes (Lutgehetmann 2011). Chimeric mice can be superinfected or
simultaneously infected with different human hepatotropic viruses to investigate the
78  Hepatology 2012
mechanisms of virus interference and response to antiviral treatment in the setting
of coinfection (Hiraga 2009).
References
Addison WR, Walters KA, Wong WW, et al. Half-life of the duck hepatitis B virus covalently
closed circular DNA pool in vivo following inhibition of viral replication. J Virol
2002;76:6356-63. (Abstract)
Azuma H, Paulk N, Ranade A, et al. Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice. Nat Biotechnol 2007;25:903-10. (Abstract)
Barker LF, Chisari FV, McGrath PP, et al. Transmission of type B viral hepatitis to
chimpanzees. J Infect Dis 1973;127(6):648-62. (Abstract)
Bartenschlager R, Schaller H. Hepadnaviral assembly is initiated by polymerase binding to the
encapsidation signal in the viral RNA genome. Embo J 1992;11:3413-20. (Abstract)
Baumert TF, Yang C, Schurmann P, et al. Hepatitis B virus mutations associated with fulminant
hepatitis induce apoptosis in primary Tupaia hepatocytes. Hepatology
2005;41(2):247-56. (Abstract)
Beck J, Nassal M. Hepatitis B virus replication. World J Gastroenterol 2007;13:48-64. (Abstract)
Belloni L, Pollicino T, De Nicola F, et al. Nuclear HBx binds the HBV minichromosome and
modifies the epigenetic regulation of cccDNA function. Proc Natl Acad Sci U S A
2009;106:19975-9. (Abstract)
Bissig KD, Wieland SF, Tran P, et al. Human liver chimeric mice provide a model for hepatitis B
and C virus infection and treatment. J Clin Invest 2010;120:924-30. (Abstract)
Block TM, Guo H, Guo JT. Molecular virology of hepatitis B virus for clinicians. Clin Liver Dis
2007;11:685-706. (Abstract)
Block TM, Lu X, Mehta AS, et al. Treatment of chronic hepadnavirus infection in a woodchuck
animal model with an inhibitor of protein folding and trafficking. Nat Med 1998;4:610-4. (Abstract)
Bock CT, Schranz P, Schroder CH, Zentgraf H. Hepatitis B virus genome is organized into
nucleosomes in the nucleus of the infected cell. Virus Genes 1994;8:215-29.
(Abstract)
Bock CT, Schwinn S, Locarnini S, et al. Structural organization of the hepatitis B virus
minichromosome. J Mol Biol 2001;307:183-96. (Abstract)
Bouchard MJ, Schneider RJ. The enigmatic X gene of hepatitis B virus. J Virol 2004;78:12725-34. (Abstract)
Bouchard MJ, Wang LH, Schneider RJ. Calcium signaling by HBx protein in hepatitis B virus
DNA replication. Science 2001;294:2376-8. (Abstract)
Brechot C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new
paradigms. Gastroenterology 2004;127(5 Suppl 1):S56-61.
Bruss V. Hepatitis B virus morphogenesis. World J Gastroenterol 2007;13:65-73. (Abstract)
Buendia MA. Hepatitis B viruses and cancerogenesis. Biomed Pharma-cother 1998;52:34-43.
(Abstract)
Chang JJ, Lewin SR. Immunopathogenesis of hepatitis B virus infection. Immunol Cell Biol
2007;85:16-23. (Abstract)
Chayama K, Hayes CN, Hiraga N, Abe H, Tsuge M, Imamura M. Animal model for study of
human hepatitis viruses. J Gastroenterol Hepatol 2011;26:13-8.
Chen HS, Kaneko S, Girones R, et al. The woodchuck hepatitis virus X gene is important for
establishment of virus infection in woodchucks. J Virol 1993;67:1218-26. (Abstract)
Chen M, Sallberg M, Hughes J, et al. Immune tolerance split between hepatitis B virus precore
and core proteins. J Virol 2005;79:3016-27. (Abstract)
Chisari FV, Isogawa M, Wieland SF. Pathogenesis of hepatitis B virus infection. Pathol Biol
(Paris);58:258-66. (Abstract)
Dagan S, Eren R. Therapeutic antibodies against viral hepatitis. Curr Opin Mol Ther
2003;5:148-55. (Abstract)
Dandri M, Burda MR, Burkle A, et al. Increase in de novo HBV DNA integrations in response to
oxidative DNA damage or inhibition of poly(ADP-ribosyl)ation. Hepatology
2002;35:217-23. (Abstract)
Dandri M, Burda MR, Torok E, et al. Repopulation of mouse liver with human hepatocytes and
in vivo infection with hepatitis B virus. Hepatology 2001;33:981-8. (Abstract)
HBV Virology  79
Dandri M, Burda MR, Will H, Petersen J. Increased hepatocyte turnover and inhibition of
woodchuck hepatitis B virus replication by adefovir in vitro do not lead to reduction of
the closed circular DNA. Hepatology 2000;32:139-46. (Abstract)
Dandri M, Burda MR, Zuckerman DM, et al. Chronic infection with hepatitis B viruses and
antiviral drug evaluation in uPA mice after liver repopulation with tupaia hepatocytes.
J Hepatol 2005;42:54-60. (Abstract)
Dandri M, Petersen J. Chimeric Mouse Model of Hepatitis B Virus infection. J Hepatol 2011.
(Abstract)
Dandri M, Petersen J. Hepatitis B virus cccDNA clearance: killing for curing? Hepatology
2005;42:1453-5. (Abstract)
Dandri M, Schirmacher P, Rogler CE. Woodchuck hepatitis virus X protein is present in
chronically infected woodchuck liver and woodchuck hepatocellular carcinomas
which are permissive for viral replication. J Virol 1996;70:5246-54. (Abstract)
Dandri M, Volz TK, Lutgehetmann M, Petersen J. Animal models for the study of HBV
replication and its variants. J Clin Virol 2005;34 Suppl 1:S54-62. (Abstract)
Daub H, Blencke S, Habenberger P, et al. Identification of SRPK1 and SRPK2 as the major
cellular protein kinases phosphorylating hepatitis B virus core protein. J Virol
2002;76:8124-37. (Abstract)
Delmas J, Schorr O, Jamard C, et al. Inhibitory effect of adefovir on viral DNA synthesis and
covalently closed circular DNA formation in duck hepatitis B virus-infected
hepatocytes in vivo and in vitro. Antimicrob Agents Chemother 2002;46:425-33.
(Abstract)
Engelke M, Mills K, Seitz S, et al. Characterization of a hepatitis B and hepatitis delta virus
receptor binding site. Hepatology 2006;43:750-60. (Abstract)
Fung SK, Lok AS. Hepatitis B virus genotypes: do they play a role in the outcome of HBV
infection? Hepatology 2004;40:790-2. (Abstract)
Funk A, Mhamdi M, Will H, Sirma H. Avian hepatitis B viruses: molecular and cellular biology,
phylogenesis, and host tropism. World J Gastroenterol 2007;13:91-103. (Abstract)
Gagneux P, Muchmore EA. The chimpanzee model: contributions and considerations for
studies of hepatitis B virus. Methods Mol Med 2004;96:289-318. (Abstract)
Glebe D, Urban S, Knoop EV, et al. Mapping of the hepatitis B virus attachment site by use of
infection-inhibiting preS1 lipopeptides and tupaia hepatocytes. Gastroenterology
2005;129:234-45. (Abstract)
Glebe D, Urban S. Viral and cellular determinants involved in hepadnaviral entry. World J
Gastroenterol 2007;13:22-38. (Abstract)
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;79:1613-22.
(Abstract)
Gripon P, Rumin S, Urban S, et al. Infection of a human hepatoma cell line by hepatitis B virus.
Proc Natl Acad Sci USA 2002;99:15655-60. (Abstract)
Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV. Viral clearance without
destruction of infected cells during acute HBV infection. Science 1999;284:825-9.
(Abstract)
Guirgis BS, Abbas RO, Azzazy HM. Hepatitis B virus genotyping: current methods and clinical
implications. Int J Infect Dis 2010;14:e941-53. (Abstract)
Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B:
natural history and treatment. Semin Liver Dis 2006;26:130-41. (Abstract)
Harrison TJ. Hepatitis B virus: molecular virology and common mutants. Semin Liver Dis
2006;26:87-96. (Abstract)
Hiraga N, Imamura M, Hatakeyama T, et al. Absence of viral interference and different
susceptibility to interferon between hepatitis B virus and hepatitis C virus in human
hepatocyte chimeric mice. J Hepatol 2009;51:1046-54. (Abstract)
Iavarone M, Trabut JB, Delpuech O, et al. Characterisation of hepatitis B virus X protein
mutants in tumour and non-tumour liver cells using laser capture microdissection. J
Hepatol 2003;39:253-61. (Abstract)
Iwarson S, Tabor E, Thomas HC, et al. Neutralization of hepatitis B virus infectivity by a murine
monoclonal antibody: an experimental study in the chimpanzee. J Med Virol
1985;16:89-96. (Abstract)
Jilbert AR, Miller DS, Scougall CA, Turnbull H, Burrell CJ. Kinetics of duck hepatitis B virus
infection following low dose virus inoculation: one virus DNA genome is infectious in
neonatal ducks. Virology 1996;226:338-45. (Abstract)
80  Hepatology 2012
Kann M, Gerlich WH. Effect of core protein phosphorylation by protein kinase C on
encapsidation of RNA within core particles of hepatitis B virus. J Virol 1994;68:7993-8000. (Abstract)
Kann M, Schmitz A, Rabe B. Intracellular transport of hepatitis B virus. World J Gastroenterol
2007;13:39-47. (Abstract)
Kann M, Sodeik B, Vlachou A, Gerlich WH, Helenius A. Phosphorylation-dependent binding of
hepatitis B virus core particles to the nuclear pore complex. J Cell Biol 1999;145:45-55. (Abstract)
Kekule AS, Lauer U, Weiss L, Luber B, Hofschneider PH. Hepatitis B virus transactivator HBx
uses a tumour promoter signalling pathway. Nature 1993;361:742-5. (Abstract)
Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver
cancer in transgenic mice. Nature 1991;351:317-20. (Abstract)
Kim SH, Shin YW, Hong KW, et al. Neutralization of hepatitis B virus (HBV) by human
monoclonal antibody against HBV surface antigen (HBsAg) in chimpanzees. Antiviral
Res 2008;79:188-91. (Abstract)
Kock J, Nassal M, MacNelly S, Baumert TF, Blum HE, von Weizsacker F. Efficient infection of
primary tupaia hepatocytes with purified human and woolly monkey hepatitis B virus.
J Virol 2001;75:5084-9. (Abstract)
Kock J, Rosler C, Zhang JJ, Blum HE, Nassal M, Thoma C. Generation of covalently closed
circular DNA of hepatitis B viruses via intracellular recycling is regulated in a virus
specific manner. PLoS Pathog 2010;6:e1001082. (Abstract)
Korba BE, Cote PJ, Menne S, et al. Clevudine therapy with vaccine inhibits progression of
chronic hepatitis and delays onset of hepatocellular carcinoma in chronic woodchuck
hepatitis virus infection. Antivir Ther 2004;9:937-52. (Abstract)
Korba BE, Cote PJ, Wells FV, et al. Natural history of woodchuck hepatitis virus infections
during the course of experimental viral infection: molecular virologic features of the
liver and lymphoid tissues. J Virol 1989;63:1360-70. (Abstract)
Lanford RE, Chavez D, Brasky KM, Burns RB, Rico-Hesse R. Isolation of a hepadnavirus from
the woolly monkey, a New World primate. Proc Natl Acad Sci U S A 1998;95:5757-61. (Abstract)
Lang T, Lo C, Skinner N, Locarnini S, Visvanathan K, Mansell A. The hepatitis B e antigen
(HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway.
J Hepatol 2011;55:762-9. (Abstract)
Laras A, Koskinas J, Dimou E, Kostamena A, Hadziyannis SJ. Intrahepatic levels and
replicative activity of covalently closed circular hepatitis B virus DNA in chronically
infected patients. Hepatology 2006;44:694-702. (Abstract)
Lee JY, Locarnini S. Hepatitis B virus: pathogenesis, viral intermediates, and viral replication.
Clin Liver Dis 2004;8:301-20. (Abstract)
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;85:11916-27. (Abstract)
Levrero M, Pollicino T, Petersen J, Belloni L, Raimondo G, Dandri M. Control of cccDNA
function in hepatitis B virus infection. J Hepatol 2009;51:581-92. (Abstract)
Liaw YF, Brunetto MR, Hadziyannis S. The natural history of chronic HBV infection and
geographical differences. Antivir Ther 2010;15 Suppl 3:25-33. (Abstract)
Lok AS. Prevention of hepatitis B virus-related hepatocellular carcinoma. Gastroenterology
2004;127(5 Suppl 1):S303-9.
Lu M, Roggendorf M. Evaluation of new approaches to prophylactic and therapeutic
vaccinations against hepatitis B viruses in the woodchuck model. Intervirology
2001;44:124-31. (Abstract)
Lucifora J, Arzberger S, Durantel D, et al. Hepatitis B virus X protein is essential to initiate and
maintain virus replication after infection. J Hepatol 2011;55:996-1003. (Abstract)
Lupberger J, Hildt E. Hepatitis B virus-induced oncogenesis. World J Gastroenterol 2007;13:74-81. (Abstract)
Lutgehetmann M, Bornscheuer T, Volz T, et al. Hepatitis B Virus Limits Response of Human
Hepatocytes to Interferon-alpha in Chimeric Mice. Gastroenterology 2011. (Abstract)
Lutgehetmann M, Mancke LV, Volz T, et al. Human chimeric uPA mouse model to study
hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology 2011.
(Abstract)
HBV Virology  81
Lutgehetmann M, Volz T, Kopke A, et al. In vivo proliferation of hepadnavirus-infected
hepatocytes induces loss of covalently closed circular DNA in mice. Hepatology
2010;52:16-24. (Abstract)
Lutgehetmann M, Volzt T, Quaas A, et al. Sequential combination therapy leads to biochemical
and histological improvement despite low ongoing intrahepatic hepatitis B virus
replication. Antivir Ther 2008;13:57-66. (Abstract)
Lutwick LI, Robinson WS. DNA synthesized in the hepatitis B Dane particle DNA polymerase
reaction. J Virol 1977;21:96-104. (Abstract)
Mason WS, Aldrich C, Summers J, Taylor JM. Asymmetric replication of duck hepatitis B virus
DNA in liver cells: Free minus-strand DNA. Proc Natl Acad Sci U S A 1982;79:3997-4001. (Abstract)
Mason WS, Cullen J, Moraleda G, et al. Lamivudine therapy of WHV-infected woodchucks.
Virology 1998;245:18-32. (Abstract)
Mason WS, Jilbert AR, Summers J. Clonal expansion of hepatocytes during chronic woodchuck
hepatitis virus infection. Proc Natl Acad Sci U S A 2005;102:1139-44. (Abstract)
Mason WS, Seal G, Summers J. Virus of Pekin ducks with structural and biological relatedness
to human hepatitis B virus. J Virol 1980;36:829-36. (Abstract)
McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009;49(5
Suppl):S45-55.
Melegari M, Wolf SK, Schneider RJ. Hepatitis B virus DNA replication is coordinated by core
protein serine phosphorylation and HBx expression. J Virol 2005;79:9810-20.
(Abstract)
Menne S, Cote PJ, Korba BE, et al. Antiviral effect of oral administration of tenofovir disoproxil
fumarate in woodchucks with chronic woodchuck hepatitis virus infection. Antimicrob
Agents Chemother 2005;49:2720-8.
Moraleda G, Saputelli J, Aldrich CE, Averett D, Condreay L, Mason WS. Lack of effect of
antiviral therapy in nondividing hepatocyte cultures on the closed circular DNA of
woodchuck hepatitis virus. J Virol 1997;71:9392-9. (Abstract)
Murray JM, Wieland SF, Purcell RH, Chisari FV. Dynamics of hepatitis B virus clearance in
chimpanzees. Proc Natl Acad Sci U S A 2005;102:17780-5. (Abstract)
Nassal M. Hepatitis B viruses: reverse transcription a different way. Virus Res 2008;134:235-49. (Abstract)
Newbold JE, Xin H, Tencza M, et al. The covalently closed duplex form of the hepadnavirus
genome exists in situ as a heterogeneous population of viral minichromosomes. J
Virol 1995;69:3350-7. (Abstract)
Ogata N, Cote PJ, Zanetti AR, et al. Licensed recombinant hepatitis B vaccines protect
chimpanzees against infection with the prototype surface gene mutant of hepatitis B
virus. Hepatology 1999;30:779-86. (Abstract)
Park IY, Sohn BH, Yu E, et al. Aberrant epigenetic modifications in hepatocarcinogenesis
induced by hepatitis B virus X protein. Gastroenterology 2007;132:1476-94.
(Abstract)
Petersen J, Dandri M, Gupta S, Rogler CE. Liver repopulation with xenogenic hepatocytes in B
and T cell-deficient mice leads to chronic hepadnavirus infection and clonal growth of
hepatocellular carcinoma. Proc Natl Acad Sci U S A 1998;95:310-5. (Abstract)
Petersen J, Dandri M, Mier W, et al. Prevention of hepatitis B virus infection in vivo by entry
inhibitors derived from the large envelope protein. Nat Biotechnol 2008;26(3):335-41.
(Abstract)
Pollicino T, Saitta C, Raimondo G. Hepatocellular carcinoma: the point of view of the hepatitis B
virus. Carcinogenesis 2011;32:1122-32. (Abstract)
Porterfield JZ, Dhason MS, Loeb DD, Nassal M, Stray SJ, Zlotnick A. Full-length hepatitis B
virus core protein packages viral and heterologous RNA with similarly high levels of
cooperativity. J Virol 2010;84:7174-84. (Abstract)
Pujol FH, Navas MC, Hainaut P, Chemin I. Worldwide genetic diversity of HBV genotypes and
risk of hepatocellular carcinoma. Cancer Lett 2009;286:80-8. (Abstract)
Pult I, Netter HJ, Bruns M, et al. Identification and analysis of a new hepadnavirus in white
storks. Virology 2001;289:114-28. (Abstract)
Quasdorff M, Hosel M, Odenthal M, et al. A concerted action of HNF4alpha and HNF1alpha
links hepatitis B virus replication to hepatocyte differentiation. Cell Microbiol
2008;10:1478-90. (Abstract)
82  Hepatology 2012
Rabe B, Glebe D, Kann M. 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 2006;80:5465-73. (Abstract)
Reaiche GY, Le Mire MF, Mason WS, Jilbert AR. The persistence in the liver of residual duck
hepatitis B virus covalently closed circular DNA is not dependent upon new viral DNA
synthesis. Virology 2010;406:286-92. (Abstract)
Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades
after patients' recovery from acute viral hepatitis despite active maintenance of a
cytotoxic T-lymphocyte response. Nat Med 1996;2:1104-8. (Abstract)
Rhim JA, Sandgren EP, Degen JL, Palmiter RD, Brinster RL. Replacement of diseased mouse
liver by hepatic cell transplantation. Science 1994;263:1149-52. (Abstract)
Roggendorf M, Schulte I, Xu Y, Lu M. Therapeutic vaccination in chronic hepatitis B: preclinical
studies in the woodchuck model. J Viral Hepat 2007;14 Suppl 1:51-7. (Abstract)
Roggendorf M, Tolle TK. The woodchuck: an animal model for hepatitis B virus infection in
man. Intervirology 1995;38:100-12. (Abstract)
Schaefer S. Hepatitis B virus taxonomy and hepatitis B virus genotypes. World J Gastroenterol
2007;13:14-21. (Abstract)
Schildgen O, Roggendorf M, Lu M. Identification of a glycosylation site in the woodchuck
hepatitis virus preS2 protein and its role in protein trafficking. J Gen Virol
2004;85:787-93. (Abstract)
Schmitt S, Glebe D, Tolle TK, et al. Structure of pre-S2 N- and O-linked glycans in surface
proteins from different genotypes of hepatitis B virus. J Gen Virol 2004;85:2045-53.
(Abstract)
Schmitz A, Schwarz A, Foss M, et al. Nucleoporin 153 arrests the nuclear import of hepatitis B
virus capsids in the nuclear basket. PLoS Pathog 2010;6:e1000741.
Schultz U, Grgacic E, Nassal M. Duck hepatitis B virus: an invaluable model system for HBV
infection. Adv Virus Res 2004;63:1-70. (Abstract)
Schulze A, Gripon P, Urban S. Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology 2007;46:1759-68.
(Abstract)
Schulze A, Mills K, Weiss TS, Urban S. Hepatocyte polarization is essential for the productive
entry of the hepatitis B virus. Hepatology 2011. (Abstract)
Schulze A, Schieck A, Ni Y, Mier W, Urban S. Fine mapping of pre-S sequence requirements
for hepatitis B virus large envelope protein-mediated receptor interaction. J Virol
2010;84:1989-2000. (Abstract)
Seeger C, Ganem D, Varmus HE. Biochemical and genetic evidence for the hepatitis B virus
replication strategy. Science 1986;232:477-84. (Abstract)
Seeger C, Mason WS. Hepatitis B virus biology. Microbiol Mol Biol Rev 2000;64:51-68.
(Abstract)
Shepard CW, Simard EP, Finelli L, Fiore AE, Bell BP. Hepatitis B virus infection: epidemiology
and vaccination. Epidemiol Rev 2006;28:112-25. (Abstract)
Slagle BL, Lee TH, Medina D, Finegold MJ, Butel JS. Increased sensitivity to the
hepatocarcinogen diethylnitrosamine in transgenic mice carrying the hepatitis B virus
X gene. Mol Carcinog 1996;15:261-9. (Abstract)
Sprengel R, Kaleta EF, Will H. Isolation and characterization of a hepatitis B virus endemic in
herons. J Virol 1988;62:3832-9. (Abstract)
Summers J, Jilbert AR, Yang W, et al. Hepatocyte turnover during resolution of a transient
hepadnaviral infection. Proc Natl Acad Sci U S A 2003;100:11652-9. (Abstract)
Summers J, Mason WS. Residual integrated viral DNA after hepadnavirus clearance by
nucleoside analog therapy. Proc Natl Acad Sci U S A 2004;101:638-40. (Abstract)
Summers J, Smith PM, Huang MJ, Yu MS. Morphogenetic and regulatory effects of mutations
in the envelope proteins of an avian hepadnavirus. J Virol 1991;65:1310-7. (Abstract)
Summers J, Smolec JM, Snyder R. A virus similar to human hepatitis B virus associated with
hepatitis and hepatoma in woodchucks. Proc Natl Acad Sci U S A 1978;75:4533-7.
(Abstract)
Summers J. The replication cycle of hepatitis B viruses. Cancer 1988;61:1957-62. (Abstract)
Tennant BC, Baldwin BH, Graham LA, et al. Antiviral activity and toxicity of fialuridine in the
woodchuck model of hepatitis B virus infection. Hepatology 1998;28:179-91.
(Abstract)
Tennant BC, Toshkov IA, Peek SF, et al. Hepatocellular carcinoma in the woodchuck model of
hepatitis B virus infection. Gastroenterology 2004;127(5 Suppl 1):S283-93. (Abstract)
HBV Virology  83
Thermet A, Buronfosse T, Werle-Lapostolle B, et al. DNA vaccination in combination or not with
lamivudine treatment breaks humoral immune tolerance and enhances cccDNA
clearance in the duck model of chronic hepatitis B virus infection. J Gen Virol
2008;89:1192-201.
Thimme R, Wieland S, Steiger C, et al. CD8(+) T cells mediate viral clearance and disease
pathogenesis during acute hepatitis B virus infection. J Virol 2003;77:68-76.
(Abstract)
Tsuge M, Hiraga N, Akiyama R, et al. HBx protein is indispensable for development of viraemia
in human hepatocyte chimeric mice. J Gen Virol 2010;91:1854-64. (Abstract)
Tsuge M, Hiraga N, Takaishi H, et al. Infection of human hepatocyte chimeric mouse with
genetically engineered hepatitis B virus. Hepatology 2005;42:1046-54. (Abstract)
Urban S, Schulze A, Dandri M, Petersen J. The replication cycle of hepatitis B virus. J Hepatol
2010;52:282-4. (Abstract)
Visvanathan K, Lewin SR. Immunopathogenesis: role of innate and adaptive immune
responses. Semin Liver Dis 2006;26:104-15. (Abstract)
Volz T, Lutgehetmann M, Wachtler P, et al. Impaired Intrahepatic Hepatitis B Virus Productivity
Contributes to Low Viremia in Most HBeAg-Negative Patients. Gastroenterology
2007;133:843-52. (Abstract)
von Weizsacker F, Kock J, MacNelly S, Ren S, Blum HE, Nassal M. The tupaia model for the
study of hepatitis B virus: direct infection and HBV genome transduction of primary
tupaia hepatocytes. Methods Mol Med 2004;96:153-61. (Abstract)
Walter E, Keist R, Niederost B, Pult I, Blum HE. Hepatitis B virus infection of tupaia hepatocytes
in vitro and in vivo. Hepatology 1996;24:1-5. (Abstract)
Werle-Lapostolle B, Bowden S, Locarnini S, et al. Persistence of cccDNA during the natural
history of chronic hepatitis B and decline during adefovir dipivoxil therapy.
Gastroenterology 2004;126:1750-8. (Abstract)
Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to
hepatitis B virus infection. Proc Natl Acad Sci U S A 2004;101:6669-74. (Abstract)
Will H, Cattaneo R, Koch HG, et al. Cloned HBV DNA causes hepatitis in chimpanzees. Nature
1982;299:740-2. (Abstract)
Wong DK, Yuen MF, Yuan H, et al. Quantitation of covalently closed circular hepatitis B virus
DNA in chronic hepatitis B patients. Hepatology 2004;40:727-37. (Abstract)
Wu TT, Coates L, Aldrich CE, Summers J, Mason WS. In hepatocytes infected with duck
hepatitis B virus, the template for viral RNA synthesis is amplified by an intracellular
pathway. Virology 1990;175:255-61. (Abstract)
Wursthorn K, Lutgehetmann M, Dandri M, et al. Peginterferon alpha-2b plus adefovir induce
strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B.
Hepatology 2006;44:675-84. (Abstract)
Yan RQ, Su JJ, Huang DR, Gan YC, Yang C, Huang GH. Human hepatitis B virus and
hepatocellular carcinoma. I. Experimental infection of tree shrews with hepatitis B
virus. J Cancer Res Clin Oncol 1996;122:283-8. (Abstract)
Yan RQ, Su JJ, Huang DR, Gan YC, Yang C, Huang GH. Human hepatitis B virus and
hepatocellular carcinoma. II. Experimental induction of hepatocellular carcinoma in
tree shrews exposed to hepatitis B virus and aflatoxin B1. J Cancer Res Clin Oncol
1996;122:289-95. (Abstract)
Yang B, Bouchard MJ. The Hepatitis B Virus X Protein Elevates Cytosolic Calcium Signals by
Modulating Mitochondrial Calcium Uptake. J Virol 2011. (Abstract)
Zhang YY, Zhang BH, Theele D, Litwin S, Toll E, Summers J. Single-cell analysis of covalently
closed circular DNA copy numbers in a hepadnavirus-infected liver. Proc Natl Acad
Sci U S A 2003;100:12372-7. (Abstract)
Zhang Z, Protzer U, Hu Z, Jacob J, Liang TJ. Inhibition of cellular pro-teasome activities
enhances hepadnavirus replication in an HBX-dependent manner. J Virol
2004;78:4566-72. (Abstract)
Zhang Z, Torii N, Hu Z, Jacob J, Liang TJ. X-deficient woodchuck hepatitis virus mutants
behave like attenuated viruses and induce protective immunity in vivo. J Clin Invest
2001;108:1523-31. (Abstract)
Zimmerman KA, Fischer KP, Joyce MA, Tyrrell DL. Zinc finger proteins designed to specifically
target duck hepatitis B virus covalently closed circular DNA inhibit viral transcription
in tissue culture. J Virol 2008;82:8013-21. (Abstract)
Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology
2009;137:1593-608 e1-2. (Abstract)
84  Hepatology 2012
Zoulim F, Saputelli J, Seeger C. Woodchuck hepatitis virus X protein is required for viral
infection in vivo. J Virol 1994;68:2026-30. (Abstract)
Zoulim F, Seeger C. Reverse transcription in hepatitis B viruses is primed by a tyrosine residue
of the polymerase. J Virol 1994;68:6-13. (Abstract)
Zoulim F. Assessment of treatment efficacy in HBV infection and disease. J Hepatol 2006;44
Suppl 1:S95-9. (Abstract)
Zoulim F. Combination of nucleoside analogues in the treatment of chronic hepatitis B virus
infection: lesson from experimental models. J Antimicrob Chemother 2005;55:608-11.
(Abstract)
Zoulim F. New insight on hepatitis B virus persistence from the study of intrahepatic viral
cccDNA. J Hepatol 2005;42:302-8. (Abstract)
HCV Virology  85
6.  HCV Virology
Bernd Kupfer
History
Hepatitis C virus (HCV) is a major cause of progressive liver disease with
approximately 130-170 million people infected worldwide. HCV induces chronic
infection in up to 80% of infected individuals. The main complications of HCV
infection are severe liver fibrosis and cirrhosis, and 30-50% of individuals with
cirrhosis go on to develop hepatocellular carcinoma (Tong 1995, Poynard 1997).
Until 1975, only two hepatitis viruses had been identified, the “infectious hepatitis
virus” (hepatitis A virus, HAV) and the “serum hepatitis virus” (hepatitis B virus,
HBV). However, other viruses were excluded from being the cause of
approximately 65% of post-transfusion hepatitis. Therefore, these hepatitis cases
were termed “non-A, non-B hepatitis” (NANBH) (Feinstone 1975). Inoculation of
chimpanzees (Pan troglodytes) with blood products derived from humans with
NANB hepatitis led to persistent increases of serum alanine aminotransferase (ALT)
indicating that an infectious agent was the cause of the disease (Alter 1978,
Hollinger 1978). Subsequently, it was demonstrated that the NANBH agent could
be inactivated by chloroform (Feinstone 1983). Moreover, it was reported that the
infectious agent was able to pass through 80 nm membrane filters (Bradley 1985).
Taken together these findings suggested that the NANBH causing agent would be a
small virus with a lipid envelope. However, the lack of a suitable cell culture system
for cultivation of the NANBH agent and the limited availability of chimpanzees
prevented further characterization of the causative agent of NANBH for several
years. In 1989, using a newly developed cloning strategy for nucleic acids derived
from plasma of NANBH infected chimpanzees the genome of the major causative
agent for NANBH was characterized (Choo 1989). cDNA clone 5-1-1 encoded
immunological epitopes that interacted with sera from individuals with NANBH
(Choo 1989, Kuo 1989). The corresponding infectious virus causing the majority of
NANBH was subsequently termed hepatitis C virus (HCV).