Subcellular localization of hepatitis B core antigen in relation to hepatocyte regeneration in chronic hepatitis B

Chu, Chia–Ming; Yeh, Chi-Ju; Sheen, I‐Shyan; Liaw, Yun–Fan

doi:10.1016/0016-5085(95)90760-2

Cited by 78 publications

(71 citation statements)

References 25 publications

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“…2C and 3). Cytoplasmic HBcAg (cHBcAg) is an indicator of HBV replication (13-15), whereas nuclear HBcAg (nHBcAg) is a highly stable species that persists in the absence of HBV replication until cells are either killed or stimulated to divide (16,17).…”

Section: Resultsmentioning

confidence: 99%

Immune effectors required for hepatitis B virus clearance

Yang

Althage

Chung

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

205

175

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To better define the mechanism(s) likely responsible for viral clearance during hepatitis B virus (HBV) infection, viral clearance was studied in a panel of immunodeficient mouse strains that were hydrodynamically transfected with a plasmid containing a replication-competent copy of the HBV genome. Neither B cells nor perforin were required to clear the viral DNA transcriptional template from the liver. In contrast, the template persisted for at least 60 days at high levels in NOD/Scid mice and at lower levels in the absence of CD4 + and CD8 + T cells, NK cells, Fas, IFN-gamma (IFN-γ), IFN-alpha/beta receptor (IFN-α/βR1), and TNF receptor 1 (TNFR1), indicating that each of these effectors was required to eliminate the transcriptional template from the liver. Interestingly, viral replication was ultimately terminated in all lineages except the NOD/Scid mice, suggesting the existence of redundant pathways that inhibit HBV replication. Finally, induction of a CD8 + T cell response in these animals depended on the presence of CD4 + T cells. These results are consistent with a model in which CD4 + T cells serve as master regulators of the adaptive immune response to HBV; CD8 + T cells are the key cellular effectors mediating HBV clearance from the liver, apparently by a Fas-dependent, perforinindependent process in which NK cells, IFN-γ, TNFR1, and IFN-α/βR play supporting roles. These results provide insight into the complexity of the systems involved in HBV clearance, and they suggest unique directions for analysis of the mechanism(s) responsible for HBV persistence.H epatitis B virus (HBV) is a noncytopathic human hepadnavirus that causes acute and chronic hepatitis and hepatocellular carcinoma (1). Approximately 350 million people worldwide are chronically infected by HBV, which greatly increases the risk of hepatocellular carcinoma (HCC) and causes more than 1 million deaths annually (2). Because HBV is not infectious in small animal or tissue culture models, systematic examination of the host-virus interactions during HBV infection has been difficult. The full spectrum of immunological requirements for HBV clearance is not completely defined.Our current understanding is based to a large extent on comparison of the immune responses mounted against HBV in patients who clear and who fail to clear HBV (3), experiments in which potential effectors of clearance (e.g., HBsAg-specific CD8 + T cells, recombinant IFN-γ and TNF-α) have been adoptively transferred to or induced in HBV transgenic mice (4-8), and a limited number of experiments conducted in HBVinfected chimpanzees (9, 10, 18). Collectively, these studies have led to the current model for clearance of acute HBV infection, namely (i) that viral clearance during HBV infection is associated with entry of CD8 + T cells into the liver, the production of IFN-γ, and the induction of inflammatory liver disease (reviewed in ref.3); (ii) that IFN-γ production, viral clearance, and liver disease are all impaired in the absence of CD8 + T cells (11); and (iii) that noncy...

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Section: Resultsmentioning

confidence: 99%

Immune effectors required for hepatitis B virus clearance

Yang

Althage

Chung

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

205

175

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“…The localization of core in humans is also variable: Akiba et al (1987) and Sharma et al (2002) observed more frequent nuclear localization while others observed a mainly cytoplasmic core and/or capsid localization (Liu et al, 2009;Michalak & Nowosławski, 1982;Park et al, 1999;Petit & Pillot, 1985). In terms of disease and viral load, the majority of studies associate cytoplasmic capsids with high hepatocellular injury (Chu et al, 1995Kim et al, 2006;Naoumov et al, 1990) and a low level viraemia (Liu et al, 2009) while nuclear dominance is associated with high viral load and minor hepatitis activity .…”

Section: Introductionmentioning

confidence: 99%

Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

Deroubaix

Osseman

Cassany

et al. 2015

Journal of General Virology

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Biopsies from patients show that hepadnaviral core proteins and capsids -collectively called core -are found in the nucleus and cytoplasm of infected hepatocytes. In the majority of studies, cytoplasmic core localization is related to low viraemia while nuclear core localization is associated with high viral loads. In order to better understand the molecular interactions leading to core localization, we analysed transfected hepatoma cells using immune fluorescence microscopy. We observed that expression of core protein in the absence of other viral proteins led to nuclear localization of core protein and capsids, while expression of core in the context of the other viral proteins resulted in a predominantly cytoplasmic localization. Analysis of which viral partner was responsible for cytoplasmic retention indicated that the HBx, surface proteins and HBeAg had no impact but that the viral polymerase was the major determinant. Further analysis revealed that e, an RNA structure to which the viral polymerase binds, was essential for cytoplasmic retention. Furthermore, we showed that core protein phosphorylation at Ser 164 was essential for the cytoplasmic core localization phenotype, which is likely to explain differences observed between individual cells.

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“…This classification of HBcAg within the hepatocytes is associated with the degree of inflammatory responses, the severity of liver cell damage and the expression of HBeAg. 5,6 In addition, HBsAg is histologically identified as cHBsAg (cytoplasmic expression), mHBsAg (membranous expression). It is known to be related to the activity of viral replication.…”

Section: Introductionmentioning

confidence: 99%

Associations of Expressions of HBcAg and HBsAg with the Histologic Activity of Liver Disease and Viral Replication

Son¹,

Yoo²,

Kwon³

et al. 2008

Gut Liver

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Background/Aims: Subcellular localization of hepatitis B virus (HBV) core antigen (HBcAg) and HBV surface antigen (HBsAg) is known to be related to the activity of liver disease and the level of HBV replication. The aim of this study was to determine the correlation between histologic activity, viral replication, and the intracellular distributions of HBcAg and HBsAg. Methods: We enrolled 670 patients with chronic hepatitis B who underwent liver biopsy at Bundang CHA hospital between 1997 to 2007. The data from medical records were reviewed retrospectively. Results: The stage of fibrosis was higher (3.31±1.34 vs. 2.43±1.39, mean±SD, p＜0.01) and the grade of necroinflammatory activity was higher (9.39±3.11 vs. 6.13±3.40, p＜0.001) for the cytoplasmic expression of HBcAg (cHBcAg) than for the nuclear expression of HBcAg (nHBcAg). The serum HBV DNA level was 677.30±983.14 pg/mL in cHBcAg, 1274.46±1417.28 pg/mL in nHBcAg, 1121.01±1121.0 pg/mL in c-nHBcAg, and 229.47±678.92 pg/mL in negative (p＜0.001). HBeAg was seropositive in 74.7% of patients with cHBcAg, 90.6% in those with nHBcAg, 90.3% in those with n-cHBcAg, and 55.6% in those with negative (p＜0.001). The histologic stage and grade of hepatitis were not significantly correlated with the subcellular localization of intrahepatic HBsAg (p＞0.05). Conclusions: These observations suggest that the histologic activity of hepatitis is higher and viral replication is lower in cHBcAg positive patients than in those with nHBcAg. (Gut and Liver 2008;2:166-173)

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Subcellular localization of hepatitis B core antigen in relation to hepatocyte regeneration in chronic hepatitis B

Cited by 78 publications

References 25 publications

Immune effectors required for hepatitis B virus clearance

Immune effectors required for hepatitis B virus clearance

Expression of viral polymerase and phosphorylation of core protein determine core and capsid localization of the human hepatitis B virus

Associations of Expressions of HBcAg and HBsAg with the Histologic Activity of Liver Disease and Viral Replication

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