A Novel Mouse Model Harboring Hepatitis B Virus Covalently Closed Circular DNA

Area of Science:

• Virology
• Hepatology
• Molecular Biology

Background:

• Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) persistence hinders effective antiviral therapy.
• Lack of suitable small animal models impedes research on HBV cccDNA formation and antiviral development.

Purpose of the Study:

• To establish a novel mouse model that supports the formation of HBV cccDNA.
• To provide a platform for studying HBV cccDNA biology and testing new antiviral strategies.

Main Methods:

• Construction of an adeno-associated virus (AAV) vector carrying a replication-deficient HBV1.04-fold genome (AAV-HBV1.04).
• Evaluation of HBV replication markers in transfected cells and in mice injected with the AAV-HBV1.04 viral vector.
• Investigation of cccDNA formation mechanisms using ATR inhibitors and HBV antiviral agents.

Main Results:

• AAV-HBV1.04 viral vector transduction, unlike plasmid transfection, successfully induced HBV cccDNA formation and replication markers in vitro and in vivo.
• cccDNA formation was dependent on ATR signaling and not directly inhibited by reverse transcription or capsid inhibitors.
• The developed AAV-HBV1.04 mouse model demonstrated long-term HBV replication and responsiveness to antiviral treatments.

Conclusions:

• The AAV-HBV1.04 mouse model facilitates de novo HBV cccDNA formation via an ATR-mediated DNA damage response.
• This model allows for the study of HBV cccDNA's role in producing viral antigens and progeny.
• The model offers a valuable platform for advancing the understanding of HBV cccDNA and developing novel HBV antivirals.