Journal of hepatology 2017 05 17() pii 10.1016/j.jhep.2017.05.010
BACKGROUND & AIMS
Studying hepatitis delta virus (HDV) and developing new treatments is hampered by the limited availability of small animal models. Here a description of a robust mouse model of HDV infection that mimics several important characteristics of the human disease is presented.
HDV- and HBV-replication competent genomes were delivered to the mouse liver using adeno-associated viruses (AAV) (AAV-HDV and AAV-HBV). Viral load, antigen expression and genomes were quantified at different time points after AAV injection. Furthermore, liver pathology, genome editing, and the activation of the innate immune response were evaluated.
AAV-HDV infection initiated HDV replication in mouse hepatocytes. Genome-editing was confirmed by the presence of small and large-HDV-antigens and sequencing. Viral replication was detected for 45 days, even after the AAV-HDV vector had almost disappeared. In the presence of HBV, HDV infectious particles were detected in serum. Furthermore, as observed in patients, co-infection was associated with the reduction of HBV antigen expression and the onset of liver damage that included the up/down-regulation of genes involved in the development of liver pathologies. HDV replication induced a sustained type-I IFN response, which was significantly reduced in immunodeficient mice and almost absent in MAVS-deficient mice.
The animal model described here reproduces important characteristics of human HDV infection and provides a valuable tool for characterizing the viral infection and for developing new treatments. Furthermore, MAVS was identified as a main player in HDV detection and adaptive immunity was found to be involved in the amplification of the innate immune response.
Co-infection with hepatitis B and D virus (HBV and HDV, respectively) often causes more severe disease than HBV alone, patients experience more aggressive hepatitis, have a higher risk of cirrhosis and decompensated liver disease, and higher mortality. While larger animal models such as chimpanzee and woodchuck have helped investigating many important aspects of HDV biology and infection, they come with many ethical and practical limitations. However, gaining more insight in HDV and developing new treatments is also hampered by limited availability of adequate immune competent small animal models and new ones are needed. Here a mouse model of HDV infection is described, which mimics several important characteristics of the human disease, such as the initiation and maintenance of replication in murine hepatocytes, genome-editing and, in the presence of HBV, generation of infectious particles. Expression of HBV antigen was reduced and liver damage was observed, both of which also found in patients. Lastly the involvement of adaptive immunity and the intracellular signalling molecule MAVS in mounting a strong and lasting innate response could be shown. Thus our model serves as a useful tool for the investigation of HDV biology and new treatments.