A concerted action of HNF4α and HNF1α links hepatitis B virus replication to hepatocyte differentiation

Quasdorff, Maria; Hösel, Marianna; Odenthal, Margarete; Zedler, Uta; Bohne, Felix; Gripon, Philippe; Dienes, Hans‐Peter; Drebber, Uta; Stippel, Dirk L.; Goeser, Tobias; Protzer, Ulrike

doi:10.1111/j.1462-5822.2008.01141.x

Cited by 70 publications

(92 citation statements)

References 52 publications

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“…Further studies are needed to investigate whether stability of the cccDNA is similarly affected in HBV-infected human hepatocytes repopulating the uPA mouse livers and whether specific factors present in the milieu of liver regeneration can directly suppress viral replication in vivo. 23,24 We considered the possibility that part of the intrahepatic viral DNA detected toward the end of the study may have originated from integrations promoted in the course of hepatocyte turnover, as has been shown in cell culture and in the woodchuck system. 9,18,25 However, viral integrations did not accumulate in chronically infected tupaia hepatocytes serially transplanted into uPA mice.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Proliferation of Hepadnavirus-Infected Hepatocytes Induces Loss of Covalently Closed Circular DNA in Mice

et al. 2010

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Chronic hepatitis B virus (HBV) infection is maintained by the presence of covalently closed circular DNA (cccDNA), the template of viral transcription and replication. In quiescent hepatocytes, cccDNA is a stable molecule that can persist throughout the hepatocyte lifespan. However, in chronic HBV infection, immunomediated cell injury and compensatory hepatocyte proliferation may favor cccDNA decline and selection of cccDNA-free cells. To investigate the impact of liver regeneration on cccDNA stability and activity in vivo, we used the urokinase-type plasminogen activator (uPA)/severe combined immunodeficiency (SCID) mouse model. Primary tupaia hepatocytes (PTHs) chronically infected with woolly monkey HBV (WM-HBV) were isolated from one highly viremic uPA/SCID chimeric mouse and transplanted into 20 uPA recipients. Expansion of transplanted PTHs and viral load changes were determined by real-time polymerase chain reaction and immunohistochemistry. Transplantation of WM-HBV infected hepatocytes led to an average of 3.8 PTH doublings within 80 days, 75% reduction of virion productivity (relaxed circular DNA/cccDNA), and lower expression levels of pregenomic RNA and hepatitis B core antigen. Remarkably, a median 2-log decline of cccDNA per cell determined during PTH proliferation was due to both dilution of the cccDNA pool among daughter cells and a 0.5-log loss of intrahepatic cccDNA loads (P 5 0.02). Intrahepatic viral DNA sequences persisting at the end of the study were mostly present as replicative intermediates and not as integrated virus. Conclusion: Cell division in the setting of liver regeneration and without administration of antiviral drugs induced strong destabilization of the cccDNA reservoir, resulting in cccDNA clearance in the great majority of chronically infected hepatocytes. (HEPATOLOGY 2010;52:16-24)

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Section: Discussionmentioning

confidence: 99%

In Vivo Proliferation of Hepadnavirus-Infected Hepatocytes Induces Loss of Covalently Closed Circular DNA in Mice

et al. 2010

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“…For relative quantification, the cDNA levels were determined relative to GAPDH gene expression and normalized to a dilution series of calibrator cDNA using the Relative Quantification Software (Roche Applied Science) as described (14).…”

Section: Generation Of Monoclonal Antibodies Against Nlrc5-twomentioning

confidence: 99%

A Role for the Human Nucleotide-binding Domain, Leucine-rich Repeat-containing Family Member NLRC5 in Antiviral Responses

Neerincx

Lautz

Menning

et al. 2010

Journal of Biological Chemistry

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“…Therefore, it was necessary to culture confluent cell layers for 7 days under conditions inducing cell differentiation (19,32). We determined cell viability before and 24 h after UV-C exposure by fluorescence microscopy ( Fig.…”

Section: Vol 84 2010 Apoptosis Of Hbv-infected Cells 11995mentioning

confidence: 99%

“…Progeny viral particles are released through the secretory pathway. The "noncytopathic" behavior of HBV has been demonstrated with stably transfected hepatoma cell lines (32,36) and with HBV-infected primary human hepatocytes (PHH) (35). The noncytopathic replication strategy explains why HBV infection per se does not cause liver damage in HBV-transgenic mice (14) or HBV carriers infected around birth and why it elicits little innate immune response (51).…”

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confidence: 99%

Apoptosis of Hepatitis B Virus-Infected Hepatocytes Prevents Release of Infectious Virus

Arzberger

Hösel

Protzer

2010

J Virol

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Apoptosis of infected cells is critically involved in antiviral defense. Apoptosis, however, may also support the release and spread of viruses. Although the elimination of infected hepatocytes is required to combat hepatitis B virus (HBV) infection, it is still unknown which consequences hepatocyte apoptosis has for the virus and whether or not it is advantageous to the virus. To study this, we designed a cell culture model consisting of both HBV-producing cell lines and primary human hepatocytes serving as an infection model. We showed that the release of mature, enveloped virions was 80% to 90% reduced 24 h after the induction of apoptosis in HBV-replicating hepatoma cells or HBV-infected hepatocytes. Importantly, HBV particles released from apoptotic hepatocytes were immature and nonenveloped and proved not to be infectious. We found an inverse correlation between the strength of an apoptotic stimulus and the infectivity of the virus particles released: the more potent the apoptotic stimulus, the higher the ratio of nonenveloped capsids to virions and the lower their infectivity. Furthermore, we demonstrated that HBV replication and, particularly, the expression of the HBx protein transcribed from the viral genome during replication do not sensitize cells to apoptosis. Our data clearly reject the hypothesis that the apoptosis of infected hepatocytes facilitates the propagation of HBV. Rather, these data indicate that HBV needs to prevent the apoptosis of its host hepatocyte to ensure the release of infectious progeny and, thus, virus spread in the liver.Human hepatitis B virus (HBV) is a small DNA virus characterized by a pronounced liver tropism. HBV replicates and assembles exclusively in hepatocytes without the need for cell disruption. Progeny viral particles are released through the secretory pathway. The "noncytopathic" behavior of HBV has been demonstrated with stably transfected hepatoma cell lines (32, 36) and with HBV-infected primary human hepatocytes (PHH) (35). The noncytopathic replication strategy explains why HBV infection per se does not cause liver damage in HBV-transgenic mice (14) or HBV carriers infected around birth and why it elicits little innate immune response (51). When the immune system becomes activated, however, inflammatory liver disease called hepatitis B becomes evident, and the infection may be cleared. Although HBV obviously does not need cell destruction to release infectious progeny, it is still debated whether HBV might sensitize the host hepatocyte to apoptosis to enhance its spread in the liver (41, 45).The viral genome (3.2 kb), consisting of a partially doublestranded, relaxed circular DNA (rcDNA), shows an extremely compact organization, with overlapping open reading frames and regulatory elements. Upon viral uptake into hepatocytes, the HBV capsid is transported to the nuclear pore complex, where the rcDNA genome is released into the nucleus. Inside the nucleus the rcDNA is converted to a covalently closed circular DNA (cccDNA) by cellular enzymes, which serves as ...

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A concerted action of HNF4α and HNF1α links hepatitis B virus replication to hepatocyte differentiation

Cited by 70 publications

References 52 publications

In Vivo Proliferation of Hepadnavirus-Infected Hepatocytes Induces Loss of Covalently Closed Circular DNA in Mice

In Vivo Proliferation of Hepadnavirus-Infected Hepatocytes Induces Loss of Covalently Closed Circular DNA in Mice

A Role for the Human Nucleotide-binding Domain, Leucine-rich Repeat-containing Family Member NLRC5 in Antiviral Responses

Apoptosis of Hepatitis B Virus-Infected Hepatocytes Prevents Release of Infectious Virus

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