Interaction of the Hepatitis B Core Antigen and the Innate Immune System

Lee, Byung O.; Tucker, Amy E.; Frelin, Lars; Sällberg, Matti; Jones, Joyce; Peters, C; Hughes, Janice; Whitacre, David C.; Darsow, Bryan; Peterson, Darrell L.; Milich, David R.

doi:10.4049/jimmunol.0803683

Cited by 76 publications

(78 citation statements)

References 52 publications

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“…Because it is likely that HBcAg1-166 still has the ability to bind pgRNA without further reverse transcription, it is possible that the C-terminal truncation of HBcAg prevents the exposure of the pgRNA, which may function as a ligand for intracellular pattern recognition receptors. The encapsidated ssRNA, rather than HBcAg itself, stimulates Toll-like receptor 7 signaling in mice (14). Moreover, the binding of the C-terminal domain of HBcAg to membrane heparin sulfate on the surfaces of macrophages, B cells, and dendritic cells mediates the breakdown of the viral capsid (15)(16)(17).…”

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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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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“…This finding was challenged by other scientists, as recombinant HBcAg was derived from a bacterial expression system with risk of contamination. 18,19 In contrast, Lee et al 20 indicated that the HBV nucleocapsid does not activate TLR2 but activates TLR7 with packaged single-stranded RNA (ssRNA) as a TLR7 agonists. However, these findings were not confirmed in other systems.…”

Section: Interaction Between Tlrs and Hbvmentioning

confidence: 99%

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Zhang

Yang

et al. 2014

Cell Mol Immunol

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It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus (HBV) infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons (IFNs) and pro-inflammatory cytokines. Experimental results from in vitro and in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T-and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.

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“…The core protein presented an inflammatory action in the liver, therefore it may be predicted that it serves a role in the fibrosis process. Furthermore, previous works demonstrated that truncation of the core from the carboxyl end reduces inflammatory property of protein (10,27). The carboxyl terminal region (aa 150-185) interacts closely with the viral RNA pre-genome or the viral DNA genome and regulates virus replication (9).…”

Section: Discussionmentioning

confidence: 99%

“…The carboxyl terminal region (aa 150-185) has previously been demonstrated to interact closely with the viral RNA pre-genome or DNA genome (9). The HBV core protein has been identified to exhibit a tendency for inflammation in the liver site, with previous studies demonstrating that truncation of the core by removing this carboxyl end reduces inflammation (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

The evaluation of fibrotic effects of the hepatitis B virus pre-core in hepatic stellate cells

et al. 2017

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Abstract. The role of the hepatitis B virus (HBV) endogenous pre-core protein in liver fibrosis is controversial. Whether the expression of the pre-core induces the activation of human stellate cells (HSCs) has not yet been reported. Plasmids expressing HBx, or pre-core protein were transfected into LX-2 cells. Subsequently, total RNA extracted and reverse transcription-quantitative polymerase chain reaction was performed to measure the fold change of collagen type I, α1 chain, α-smooth muscle actin and TIMP metalloproteinase inhibitor-1. Moreover, transforming growth factor (TGF)-β in the supernatant of HSCs was evaluated by ELISA assay. In addition, a MTT assay was performed to test the cytotoxicity of the endogenous expression in LX-2 cells. None of the plasmids exhibited cytotoxic nor significant proliferative effects on LX-2 cells by MTT assessment. The gene expression analysis of fibrotic genes in LX-2 cells demonstrated that the pre-core protein presented no significant (P>0.05) fibrotic impact when compared to the empty control plasmid and HBx. The data from the TGF-β ELISA was consistent with the mRNA expression as detected with the control plasmid (P>0.05). The endogenous expression of the HBV pre-core exhibited no fibrotic impression in HSCs when compared to HBx.

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Interaction of the Hepatitis B Core Antigen and the Innate Immune System

Cited by 76 publications

References 52 publications

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

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

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

The evaluation of fibrotic effects of the hepatitis B virus pre-core in hepatic stellate cells

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