3D human liver organoids: An in vitro platform to investigate HBV infection, replication and liver tumorigenesis

Hepatitis B Virus (HBV) infection is a leading cause of chronic liver cirrhosis and hepatocellular carcinoma (HCC) with an estimated 400 million people infected worldwide. The precise molecular mechanisms underlying HBV replication and tumorigenesis have remained largely uncharacterized due to the lack of a primary cell model to study HBV, a virus that exhibits stringent host species and cell-type specificity. Organoid technology has recently emerged as a powerful tool to investigate human diseases in a primary 3D cell-culture system that maintains the organisation and functionality of the tissue of origin. In this review, we describe the utilisation of human liver organoid platforms to study HBV. We first present the different categories of liver organoids and their demonstrated ability to support the complete HBV replication cycle. We then discuss the potential applications of liver organoids in investigating HBV infection and replication, related tumorigenesis and novel HBV-directed therapies. Liver organoids can be genetically modified, patient-derived, expanded and biobanked, thereby serving as a clinically-relevant, human, primary cell-derived platform to investigate HBV. Finally, we provide insights into the future applications of this powerful technology in the context of HBV-infection and HCC.