Immune Tolerance Split between Hepatitis B Virus Precore and Core Proteins

Chen, Margaret; Sällberg, Matti; Hughes, Janice; Jones, Joyce; Guidotti, Luca G.; Chisari, Francis V.; Billaud, Jean Noël; Milich, David R.

doi:10.1128/jvi.79.5.3016-3027.2005

Cited by 199 publications

(163 citation statements)

References 55 publications

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“…Second, the levels of serum HBeAg in the mice receiving hydrodynamic injections of pAAV/HBV1.2 and the HBeAg-transgenic mice may not be equivalent. Indeed, it is clear that the levels of serum HBeAg influence the potency of HBeAg in inducing T-cell tolerance (24). Taken together, these data suggest that some mechanisms other than the immunoregulatory functions of HBeAg contribute to the establishment of HBV persistence in this mouse model.…”

Section: Discussionmentioning

confidence: 62%

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: 62%

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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“…In addition to HBV DNA, HBeAg is also a serological marker for viral replication, which plays a crucial role in chronicity of HBV infection and high viral load, by inducing immunological tolerance to HBV in the fetus. The tolerance-inducing effect of HBeAg has been well characterized in mice [41][42][43] and likely contributes to the low level of core-specific T-cell responses present in HBeAgpositive CHB patients [4,5] . Clinical evidence supports the tolerogenic effect of HBeAg [5,44] .…”

Section: Figurementioning

confidence: 99%

Effect of viral load on T-lymphocyte failure in patients with chronic hepatitis B

You¹,

Sriplung²,

Geater³

et al. 2008

WJG

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AIM:To investigate peripheral T-lymphocyte subpopulation profile and its correlation with hepatitis B virus (HBV) replication in patients with chronic hepatitis B (CHB). METHODS:Distribution of T-lymphocyte subpopulations in peripheral blood was measured by flow cytometry in 206 CHB patients. HBV markers were detected with ELISA. Serum HBV DNA load was assessed with quantitative real-time polymerase chain reaction (PCR). The relationship between HBV replication and variation in peripheral T-cell subsets was analyzed. showed a similar pattern of these parameters was significantly associated with high viral load, presence of serum hepatitis B e antigen (HBeAg) expression, liver disease severity, history of maternal HBV infection, and young age at HBV infection, all with P < 0.01. There was a significant linear relationship between viral load and these parameters of T-lymphocyte subpopulations (linear trend test P < 0.001). There was a negative correlation b e t w e e n t h e l e ve l s o f C D 3 + a n d C D 4 + c e l l s a n d CD4 + /CD8 + ratio and serum level of viral load in CHB patients (r = -0.68, -0.65 and -0.75, all P < 0.0001), and a positive correlation between CD8 + cells and viral load (r = 0.70, P < 0.0001). There was a significant decreasing trend in CD3 + and CD4 + cells and CD4 + /CD8 + ratio with increasing severity of hepatocyte damage and decreasing age at HBV infection (linear trend test P < 0.01). In multiple regression (after adjustment for age at HBV infection, maternal HBV infection status and hepatocyte damage severity) log copies of HBV DNA maintained a highly significant predictive coefficient on T-lymphocyte subpopulations, and was the strongest predictor of variation in CD3 + , CD4 + , CD8 + cells and CD4 + /CD8 + ratio. However, the effect of HBeAg was not significant. RESULTS CONCLUSION:T-lymphocyte failure was significantly associated with viral replication level. The substantial linear dose-response relationship and strong independent predictive effect of viral load on T-lymphocyte subpopulations suggests the possibility of a causal relationship between them, and indicates the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients.

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“…16 HBeAg and the viral nucleocapsid, hepatitis B core antigen (HBcAg), share Ͼ90% of amino acids and have been found to be cross-reactive at the T-cell level. 17 As HBeAg is secreted from hepatocytes, it is thought that it has a central role as a tolerogen during HBV infection. This has been demonstrated in vertical HBV transmission, in which secreted HBeAg appears to be central to the induction of immunological tolerance in utero.…”

mentioning

confidence: 99%

Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion

et al. 2008

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Immune Tolerance Split between Hepatitis B Virus Precore and Core Proteins

Abstract: The function of the hepatitis B virus (HBV) precore or HBeAg is largely unknown because it is not required for viral assembly, infection, or replication. However, the HBeAg does appear to play a role in viral persistence.

Cited by 199 publications

References 55 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

Effect of viral load on T-lymphocyte failure in patients with chronic hepatitis B

Programmed death 1 expression during antiviral treatment of chronic hepatitis B: Impact of hepatitis B e-antigen seroconversion

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