A murine model of hepatitis B-associated hepatocellular carcinoma generated by adeno-associated virus-mediated gene delivery

Huang, Yeou‐Lih; Fang, Cheng; Tsuneyama, Koichi; Chou, Ho Yuan; Pan, Wen; Shih, Yao Ming; Wu, Ping; Chen, Yin; Leung, Patrick S.C.; Gershwin, M. Eric; Tao, Mi Hua

doi:10.3892/ijo.2011.1145

Cited by 19 publications

(16 citation statements)

References 41 publications

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“…In addition, 100% of these mice (12 out of 12) developed visible tumor nodules in the liver within 16 weeks. 26 We did not observe any tumor formation in 33 HBV-infected mice that had been monitored for more than 1 year, although we used the same HBV strain (a genotype D virus). In our study, one AAV construct containing the entire HBV genome was used, whereas Tao et al .…”

Section: Discussionmentioning

confidence: 90%

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A mouse model for HBV immunotolerance and immunotherapy

et al. 2013

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Lack of an appropriate small animal model remains a major hurdle for studying the immunotolerance and immunopathogenesis induced by hepatitis B virus (HBV) infection. In this study, we report a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus (AAV) carrying a replicable HBV genome (AAV/HBV). Similar to the clinical HBV carriers, the mice infected with AAV/HBV were sero-negative for antibodies against HBV surface antigen (HBsAg). Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response against HBV in these mice. To identify a vaccine that can potentially circumvent this tolerance, the TLR9 agonist CpG was added to HBsAg as an adjuvant. Vaccination of mice with HBsAg/CpG induced not only clearance of viremia, but also strong antibody production and T-cell responses. Furthermore, both the DNA replication and protein expression of HBV were significantly reduced in the livers of AAV/HBV-infected mice. Accordingly, AAV/HBV-infected mice may be used as a robust model for investigating the underlying mechanism(s) of HBV immunotolerance and for developing novel immunotherapies to eradicate HBV infections.

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Section: Discussionmentioning

confidence: 90%

“…In our study, one AAV construct containing the entire HBV genome was used, whereas Tao et al . 27 used two AAVs each containing one half of the HBV genome. However, whether this difference in AAV constructs contributes to liver cancer formation remains to be determined in the future.…”

Section: Discussionmentioning

confidence: 99%

A mouse model for HBV immunotolerance and immunotherapy

et al. 2013

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“…In addition, the effect of miR-15b down-regulation on HBV was observed in a persistent HBV expression mouse model: rAAV8–1.3HBV infected-mouse (22,23). We first evaluated the efficiency of pCAGGs-15b transduction after hydrodynamic injection and found that pCAGGs-15b was able to effectively inhibit in vivo expression of endogenous miR-15b, while it promoted in vivo expression of HNF1α, the target of miR-15b (Supplementary Figure S2A and S2B).…”

Section: Resultsmentioning

confidence: 99%

“…rAAV8–1.3HBV-transduced mouse model: HBV persistent replication with recombinant Adeno-Associated Virus 8 (AAV, serotype 8) carrying 1.3 copies of HBV genome (rAAV8–1.3HBV) was induced by tail vein injection of rAAV8–1.3HBV (1 × 10 11 vg/200 μl/mouse) (22,23). …”

Section: Methodsmentioning

confidence: 99%

Modulation of HBV replication by microRNA-15b through targeting hepatocyte nuclear factor 1α

Dai

Zhang

et al. 2014

Nucleic Acids Research

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Hepatitis B virus (HBV) infection remains a major health problem worldwide. The role played by microRNAs (miRNAs) in HBV replication and pathogenesis is being increasingly recognized. In this study, we found that miR-15b, an important miRNA during HBV infection and hepatocellular carcinoma development, directly binds hepatocyte nuclear factor 1α (HNF1α) mRNA, a negative regulator of HBV Enhancer I, to attenuate HNF1α expression, resulting in transactivation of HBV Enhancer I, in turn causing the enhancement of HBV replication and expression of HBV antigens, including HBx protein, finally leading to the down-regulated expression of miR-15b in both cell lines and mice in a long cascade of events. Our research showed that miR-15b promotes HBV replication by augmenting HBV Enhancer I activity via direct targeting HNF1α, while HBV replication and antigens expression, particularly the HBx protein, then repress the expression of miR-15b. The reciprocal regulation between miR-15b and HBV controls the level of HBV replication and might play a role in persistent HBV infection. This work adds to the body of knowledge concerning the complex interactions between HBV and host miRNAs.

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“…Many researchers have established HBV replication models in immunocompetent nontransgenic mice by employing hydrodynamic injection [36] or adenoviral vector delivery [37], [38], but in most cases only acute hepatitis can be demonstrated, and the HBV infection is eventually cleared. Persistent HBV replication in a mouse model has been demonstrated only under special conditions in which the HBV DNA was cloned in an adeno-associated viral (AAV) vector and then delivered to mouse livers either via hydrodynamic injection [39] or via AAV infection [40]. The mechanism for this persistence is partly dependent on the AAV vector, which has been shown to be poorly detected by host innate immunity and favors long-term persistence in the cells [41], [42].…”

Section: Discussionmentioning

confidence: 99%

Persistent Hepatitis B Viral Replication in a FVB/N Mouse Model: Impact of Host and Viral Factors

Chen

Kao

et al. 2012

PLoS ONE

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The mechanism underlying the chronicity of hepatitis B virus (HBV) infection has long been an interesting question. However, this mechanism remains unclear largely due to the lack of an animal model that can support persistent HBV replication and allow for the investigation of the relevant immune responses. In this study, we used hydrodynamic injection to introduce HBV replicon DNA into the livers of three different mouse strains: BALB/c, C57BL/6, and FVB/N. Interestingly, we found that an HBV clone persistently replicated in the livers of FVB/N mice for up to 50 weeks but was rapidly cleared from the livers of BALB/c and C57BL/6 mice. Flow cytometric analysis and quantitative reverse transcription PCR analysis of the mouse livers indicated that after DNA injection, FVB/N mice had few intrahepatic activated cytotoxic T lymphocytes (CTLs) and produced low levels of alanine aminotransferase, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and the CXCL9 and CXCL10 chemokines. These findings were in sharp contrast with those observed in BALB/c and C57BL/6 mice, reflecting a strong correlation between the degree of liver inflammation and viral clearance. Mutational analysis further demonstrated that a change of Asn-214 to Ser-214 in the HBV surface antigen rendered the persistent HBV clone clearable in FVB/N mice, which was accompanied by increased levels of activated CTL and upregulated expression of IFN-γ, CXCL9, and CXCL10 in the livers. These results indicate that the heterogeneity of the host factors and viral sequences may influence the immune responses against HBV. An inadequate activation of immune or inflammatory responses can lead to persistent HBV replication in vivo.

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A murine model of hepatitis B-associated hepatocellular carcinoma generated by adeno-associated virus-mediated gene delivery

Cited by 19 publications

References 41 publications

A mouse model for HBV immunotolerance and immunotherapy

A mouse model for HBV immunotolerance and immunotherapy

Modulation of HBV replication by microRNA-15b through targeting hepatocyte nuclear factor 1α

Persistent Hepatitis B Viral Replication in a FVB/N Mouse Model: Impact of Host and Viral Factors

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