Biologic and prognostic significance of hepatocyte hepatitis B core antigen expressions in the natural course of chronic hepatitis B virus infection

Hsu, Hey-Chi; Su, Ih‐Jen; Lai, Ming‐Yang; Chen, Ding‐Shinn; Chang, Mei–Hwei; Chuang, Sou-Ming; Sung, Juei‐Low

doi:10.1016/s0168-8278(87)80060-0

Cited by 111 publications

(86 citation statements)

References 20 publications

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“…It is known that there is a close relationship between these indicators. [1][2][3][4] Among them, HBcAg plays a role as the major antigen for viral immune responses. It can be histologically classified into cHBcAg (cytoplasmic expression), nHBcAg (nuclear expression) and c-nHBcAg (both cytoplasmic and nuclear expression).…”

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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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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“…It has been demonstrated that HBx transactivates the transcription of the major HBV genes, including HBcAg (4,18). Furthermore, some patients in the inactive viral replication phase of chronic hepatitis B infections do not express HBcAg in their liver (19), suggesting that the lack of HBcAg may contribute to HBV persistence. In this model, knockout of the HBx gene dramatically reduced the HBV tran- scripts.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus core antigen determines viral persistence in a C57BL/6 mouse model

Lin

Huang

Yang³

et al. 2010

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

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We recently developed a mouse model of hepatitis B virus (HBV) persistence, in which a single i.v. hydrodynamic injection of HBV DNA to C57BL/6 mice allows HBV replication and induces a partial immune response, so that about 20-30% of the mice carry HBV for more than 6 months. The model was used to identify the viral antigen crucial for HBV persistence. We knocked out individual HBV genes by introducing a premature termination codon to the HBV core, HBeAg, HBx, and polymerase ORFs. The specific-genedeficient HBV mutants were hydrodynamically injected into mice and the HBV profiles of the mice were monitored. About 90% of the mice that received the HBcAg-mutated HBV plasmid exhibited high levels of hepatitis B surface antigenemia and maintained HBsAg expression for more than 6 months after injection. To map the region of HBcAg essential for viral clearance, we constructed a set of serial HBcAg deletion mutants for hydrodynamic injection. We localized the essential region of HBcAg to the carboxyl terminus, specifically to the 10 terminal amino acids (HBcAg176-185). The majority of mice receiving this HBV mutant DNA did not elicit a proper HBcAg-specific IFN-γ response and expressed HBV virions for 6 months. These results indicate that the immune response triggered in mice by HBcAg during exposure to HBV is important in determining HBV persistence.hepatitis B surface antigenemia | hydrodynamic injection P ersistent hepatitis B virus (HBV) infections affect about 350 million people worldwide and are a major health problem. Factors directing the infection toward chronicity have been studied extensively. The exposure of neonates or young children to a high HBV viral load, together with hepatitis B e antigen (HBeAg), predicts a high rate of persistent HBV infection. A recent genomewide association study identified HLA-DP polymorphisms as another factor in the persistence of HBV infections (1). Nevertheless, the immune mechanisms that lead to HBV persistence have not been resolved. To address this issue, a commonly used mouse model, such as the HBV transgenic mouse, has been used to study the possible mechanisms. However, the main drawback of HBV transgenic mouse models is that they are immunologically tolerant of viral antigens. Therefore, to explore the issue of HBV persistence, the adoptive transfer of HBV-primed immune cells or other manipulations must be used to overcome this tolerance. Another alternative is to introduce the HBV genome into the mouse liver by hydrodynamic injection through the tail vein. With this approach, HBV was shown to replicate in the mouse liver, and the immune responses against HBV proteins to clear the HBV infection could be documented in 1-2 weeks after the injection (2). Recently, we improved this approach by modifying the HBV DNA plasmid and injecting the plasmid into C57BL/6 mice and succeeded in delaying the mouse immune clearance of HBV (3). Clearance could be postponed for 6-8 weeks and about 10-30% of the injected mice maintained HBV persistence even up to 6 months after injection...

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“…Both liver and mononuclear cells were counted and washed three times with free RPMI. (13,14), and they may also have HLA class I antigen expression on the membrane (16); ( b ) 10 5 cells/well of irradiated (8,000 rad) autologous HBV-transfected EBV-B cells as feeder cells and stimulators; and ( c ) a mixture containing recombinant human IL-2 (20 ng/ml) and IL-4 (1,000 pg/ml) (both from R&D Systems, Minneapolis, MN). After incubation at 37 Њ C in humidified 5% CO 2 atmosphere for 7 d, liver-derived T lymphocyte blasts were harvested, counted, and then cloned by limiting dilutions at 0, 50, 100, 200, 400, 800, and 1,600 cells/well in each plate of 96-well flat-bottomed tray.…”

Section: Detection Of Antigenic Peptides By Ctlmentioning

confidence: 99%

“…In vitro studies have shown that hepatitis B surface antigen (HBsAg)-and hepatitis B core antigen (HBcAg)-expressing transfectants can serve as targets for MHC class I-restricted cytotoxic T lymphocytes (CTLs) that are generated from both acute and chronic hepatitis B patients (5)(6)(7)(8)(9)(10)(11)(12). In addition, expression of HBcAg in the cytoplasm and on the membrane of liver cells is positively correlated with the hepatitis activity (13,14). Also, acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to HBcAg and hepatitis B e antigen (HBeAg), but not to HBsAg (15).…”

Section: Introductionmentioning

confidence: 99%

Purification and characterization of a naturally processed hepatitis B virus peptide recognized by CD8+ cytotoxic T lymphocytes.

Tsai

Chen²,

Yeh³

et al. 1996

J. Clin. Invest.

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Biologic and prognostic significance of hepatocyte hepatitis B core antigen expressions in the natural course of chronic hepatitis B virus infection

Cited by 111 publications

References 20 publications

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

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

Hepatitis B virus core antigen determines viral persistence in a C57BL/6 mouse model

Purification and characterization of a naturally processed hepatitis B virus peptide recognized by CD8+ cytotoxic T lymphocytes.

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