Three-dimensional culture models of hepatitis B virus infection: Progress, challenges, and opportunities

Each year, approximately 1.2 million new cases of hepatitis B are recorded globally, caused by the hepatitis B virus (HBV). This underscores the persistent transmission of the disease despite widespread availability of an effective vaccine. Although current drugs can reduce the chances of severe disease, they are not curative. Physiologically relevant in vitro models of HBV infection are essential to understand the biology of HBV and to develop strategies to target the virus. Until recently, only primary human hepatocytes could be infected with HBV. The discovery of the HBV receptor, the sodium taurocholate co-transporting polypeptide, resulted in the development of several immortalised cell lines that are infectable by HBV. These have made significant contributions to hepatitis B research. However, 2-D cell culture models fail to fully capture the complexity of the liver and HBV infection. The recent development of 3-D culture technologies offers new possibilities for modelling all the steps of HBV replication in cell culture and mimicking the liver microenvironment. This review discusses recent progress in developing models of HBV infection in 3-D cell culture and their contributions to HBV biology research and novel drug development.