A hepatitis B virus transgenic mouse model with a conditional, recombinant, episomal genome

Area of Science:

• Hepatology and Virology
• Transgenic Animal Models
• Molecular Biology

Background:

• Current hepatitis B virus (HBV) transgenic mouse models have limitations, including the absence of covalently closed circular DNA (cccDNA) and the inability to achieve a cure due to integrated viral genomes.
• Developing effective HBV therapies is hindered by the lack of suitable small animal models that replicate chronic infection and allow for potential clearance.

Purpose of the Study:

• To develop a novel transgenic mouse model (HBV1.1X) that overcomes the limitations of existing models by enabling the generation of excisable, circular HBV DNA.
• To establish a model that mimics chronic HBV infection with neonatal expression and tolerance, and allows for on-demand modulation of viral gene expression.

Main Methods:

• Generation of the HBV1.1X transgenic mouse model with an excisable HBV 1.1-mer cassette integrated into the ROSA26 locus, utilizing Cre/LoxP technology.
• Induction of recombinant cccDNA (rcccDNA) formation and modulation of HBV antigen expression (HBsAg, HBc) through viral or transgenic Cre expression.
• Administration of adenovirus expressing Cre to induce rcccDNA excision and subsequent immune response for HBV clearance demonstration.

Main Results:

• Successful induction of rcccDNA formation and regulation of HBsAg and HBc expression in HBV1.1X mice using Cre recombinase.
• Demonstrated downregulation of baseline HBsAg levels with tamoxifen-inducible Cre, indicating control over viral gene expression.
• Significant reduction in HBsAg and core antigen levels following Cre-mediated rcccDNA excision and immune response, indicating potential for HBV clearance.

Conclusions:

• The HBV1.1X mouse model is the first Cre-regulatable transgenic model for HBV, offering a valuable tool for studying chronic HBV infection.
• This model facilitates neonatal expression and tolerance of HBV antigens, with the ability to modulate HBV expression on demand.
• The HBV1.1X model provides a platform for testing curative therapies by enabling the excision of HBV DNA and subsequent immune-mediated clearance.