Advances and perspectives in animal models of human hepatitis A virus

Hepatitis A virus (HAV) is an important pathogen that has continuously posed a threat to global public health for over 5000 years. The development of accessible and reliable small animal models, especially murine models, is essential for elucidating HAV pathogenesis and advancing preventive and therapeutic strategies. The first mouse model for HAV infection was established using human-liver chimeric mice, which supported robust viral replication and high viral loads. Later, an Ifnar1^-/- mice model was established with a specific mouse-adapted strain, recapitulating key clinical features of human hepatitis A. Recently, to overcome limitations associated with the difficulty in obtaining and amplifying stocks of HAV for animal models, our laboratory established a novel hepatitis A mouse model using lipid nanoparticle-encapsulated viral genomic RNA (LNP-vRNA). This approach provides a new strategy for modeling infections of hard-to-culture RNA viruses. In this review, we systematically summarize and compare these mouse models, respectively highlighting their advantages and limitations, and offer guidance for their application in future HAV research.