In vivo and in vitro Models of Hepatitis B Virus Infection

Hepatitis B virus (Orthohepadnavirus hominoidei, HBV) is a hepatotropic virus from the Hepadnaviridae family and the causative agent of both acute and chronic hepatitis B (CHB). The possible outcomes of CHB include liver cirrhosis and hepatocellular carcinoma (HCC) that pose a significant burden on the healthcare systems worldwide. In the nuclei of infected hepatocytes of patients with CHB, the HBV genome persists as a pool of covalently closed circular DNA (cccDNA) molecules. Current therapeutic strategies cannot directly target cccDNA. Instead, the available treatments focus on long-term suppression of viral replication and require lifelong administration. Development and evaluation of novel antiviral agents capable of achieving complete HBV eradication require relevant in vivo and in vitro models of HBV infection. Among the available animal models, the following categories are distinguished: (i) animals naturally susceptible to HBV; (ii) surrogate models using animal species susceptible to the related hepadnaviruses; (iii) non-susceptible animals receiving HBV genome via recombinant viral vectors; (iv) models utilizing human hepatocyte xenografts. Among the available in vitro models, primary human and northern treeshrew (Tupaia belangeri) hepatocytes fully support the HBV replication cycle, but they rapidly lose susceptibility to the virus in cell culture. In turn, unmodified human hepatoma cell lines are not susceptible to HBV but can support viral replication after transfection with the viral genome. This review discusses key characteristics, advantages, limitations, and areas of application of the currently available in vivo and in vitro models of HBV infection.