Role of B cells in antigen presentation of the hepatitis B core

Milich, David R.; Chen, Margaret; Schödel, Florian; Peterson, Darrell L.; Jones, Joyce; Hughes, Janice

doi:10.1073/pnas.94.26.14648

Cited by 181 publications

(125 citation statements)

References 36 publications

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“…1 A and C) and other systems (20). Previous studies have demonstrated that HBeAg exhibits some immunoregulatory functions (20,21). However, we failed to observe any immunoregulatory effect of HBeAg in our model (Fig.…”

Section: Discussioncontrasting

confidence: 50%

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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: Discussioncontrasting

confidence: 50%

“…1 A and C) and other systems (20). Previous studies have demonstrated that HBeAg exhibits some immunoregulatory functions (20,21).…”

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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“…After washing, the cells were counted and distributed at 2 × 10 6 cells/mL in 10 mL RPMI FCS in 25 cm 2 flasks (Nalge-Nunc, Rochester, NY, USA) and stimulated with 10 mg/mL of peptide S (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) . After culturing for 4 days in 5% CO 2 , half of the total medium was substituted and new medium containing 2 × 10 4 U/mL of IL-2 was added.…”

Section: In Vitro Re-stimulation Of Primed Ctlmentioning

confidence: 99%

“…The cells were extensively washed with medium, resuspended in RPMI-1640 (Gibco, Scotland, UK) supplemented with 10% FCS, 2 mmol/L glutamine, 2 mmol/L piruvate, 50 mmol/L 2-mercaptoethanol and antibiotics (complete medium) and counted. Meanwhile, H-2 d mastocytome cells p815 were pulsed for 1 h at 37 ° C, 5% CO 2 in complete medium with 10 mmol/L S (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) peptide IPQSLDSWWTSL from HBsAg. 33 After incubation p815 cells were further incubated for another 15 min with Mitomycin C (Sigma).…”

Section: Preparation Of Target and Effector Cellsmentioning

confidence: 99%

“…immunization with HBsAg in alum. The IFN-γ ELISPOT assay was conducted using the immunodominant HBs (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) CTL peptide from HBsAg as previously described. Measurement of lymphoproliferative activity revealed the induction of strong proliferative responses in systemic compartments against both HBsAg and HBcAg after nasal-combined immunization.…”

Section: Lymphoproliferative and Ifn-γ Responses After Nasal Or Im mentioning

confidence: 99%

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Development of a nasal vaccine for chronic hepatitis B infection that uses the ability of hepatitis B core antigen to stimulate a strong Th1 response against hepatitis B surface antigen

et al. 2004

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SummaryThere are estimated to be 350 million chronic carriers of hepatitis B infection worldwide. Patients with chronic hepatitis B are at risk of liver cirrhosis with associated mortality because of hepatocellular carcinoma and other complications. An important goal, therefore, is the development of an effective therapeutic vaccine against chronic hepatitis B virus (HBV). A major barrier to the development of such a vaccine is the impaired immune response to HBV antigens observed in the T cells of affected patients. One strategy to overcome these barriers is to activate mucosal T cells through the use of nasal vaccination because this may overcome the systemic immune downregulation that results from HBV infection. In addition, it may be beneficial to present additional HBV epitopes beyond those contained in the traditional hepatitis B surface antigen (HbsAg) vaccine, for example, by using the hepatitis B core antigen (HBcAg). This is advantageous because HBcAg has a unique ability to act as a potent Th1 adjuvant to HbsAg, while also serving as an immunogenic target. In this study we describe the effect of coadministration of HBsAg and HBcAg as part of a strategy to develop a more potent and effective HBV therapeutic vaccine.

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Serological pattern ?anti-HBc alone?: Report on a workshop

et al. 2000

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In areas with low hepatitis B virus (HBV) endemicity such as most parts of Europe and the United States "anti-HBc alone" is found in 10-20% of all individuals with HBV markers, i.e., 1-4% of the population. In about 10% of these individuals HBV DNA is detected by PCR, the proportions varying greatly depending on the population studied, being highest in individuals coinfected with hepatitis C virus (HCV) (above 35%) and HIV (above 85%). A small proportion of individuals with "anti-HBc alone" are in the window phase of an HBV infection or in a stage of late HBV immunity. For the large proportion of these individuals this is not the case and they are thought to have an unresolved HBV-infection or a chronic infection in a late or "low grade" productive state. Currently, limited studies have been performed concerning the clinical aspects of individuals with "anti-HBc alone" and suspected chronic HBV infection. The majority of these individuals seem to be healthy. Some chronic carriers with "anti-HBc alone," however, do present signs of chronic hepatitis. Individuals with "anti-HBc alone" are potentially infectious. This is exemplified by a few case reports of HBV transmission to sexual contacts, perinatal transmission between mother and newborns and in blood recipients. Recommendations are given in relation to both the diagnostic and therapeutic procedures in the individuals with "anti-HBc alone" and in the blood banking and transplantation services.

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Role of B cells in antigen presentation of the hepatitis B core

Abstract: The hepatitis B virus (HBV) nucleocapsid or core antigen (HBcAg) is extremely immunogenic during infection and after immunization.

Cited by 181 publications

References 36 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

Development of a nasal vaccine for chronic hepatitis B infection that uses the ability of hepatitis B core antigen to stimulate a strong Th1 response against hepatitis B surface antigen

Serological pattern ?anti-HBc alone?: Report on a workshop

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