Lester Suárez-Amarán1, Carla Usai1, Marianna Di Scala1, Cristina Godoy2, Yi Ni3, Mirja Hommel1, Laura Palomo1, Víctor Segura4, Cristina Olagüe1, Africa Vales1, Alicia Ruiz-Ripa2, Maria Buti2, Eduardo Salido5, Jesús Prieto6, Stephan Urban3, Francisco Rodríguez-Frias2, Rafael Aldabe1, Gloria González-Aseguinolaza7. 1. Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain. 2. Centro de Investigación Biomédica en red: Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Virology Unit, Department of Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. 3. Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany. 4. Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain; Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. 5. Department of Pathology, Centre for Biomedical Research on Rare Diseases (CIBERER), La Laguna, S/C Tenerife, Spain. 6. Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain; Centro de Investigación Biomédica en red: Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Pamplona, Spain. 7. Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Calle Irunlarrea 3, Pamplona 31008, Spain. Electronic address: ggasegui@unav.es.
Abstract
BACKGROUND & AIMS: Studying hepatitis delta virus (HDV) and developing new treatments is hampered by the limited availability of small animal models. Herein, a description of a robust mouse model of HDV infection that mimics several important characteristics of the human disease is presented. METHODS: HDV and hepatitis B virus (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. RESULTS: 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 45days, 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 alteration of genes involved in the development of liver pathologies. HDV replication induced a sustained type I interferon response, which was significantly reduced in immunodeficient mice and almost absent in mitochondrial antiviral signaling protein (MAVS)-deficient mice. CONCLUSION: 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. Lay summary: Co-infection with hepatitis B and D virus (HBV and HDV, respectively) often causes a more severe disease condition than HBV alone. Gaining more insight into HDV and developing new treatments is 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. Lastly, the involvement of an adaptive immunity and the intracellular signaling molecule MAVS in mounting a strong and lasting innate response was shown. Thus, our model serves as a useful tool for the investigation of HDV biology and new treatments.
BACKGROUND & AIMS: Studying hepatitis delta virus (HDV) and developing new treatments is hampered by the limited availability of small animal models. Herein, a description of a robust mouse model of HDV infection that mimics several important characteristics of the human disease is presented. METHODS:HDV and hepatitis B virus (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. RESULTS: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 45days, 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 alteration of genes involved in the development of liver pathologies. HDV replication induced a sustained type I interferon response, which was significantly reduced in immunodeficientmice and almost absent in mitochondrial antiviral signaling protein (MAVS)-deficient mice. CONCLUSION: The animal model described here reproduces important characteristics of humanHDV 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. Lay summary: Co-infection with hepatitis B and D virus (HBV and HDV, respectively) often causes a more severe disease condition than HBV alone. Gaining more insight into HDV and developing new treatments is 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. Lastly, the involvement of an adaptive immunity and the intracellular signaling molecule MAVS in mounting a strong and lasting innate response was shown. Thus, our model serves as a useful tool for the investigation of HDV biology and new treatments.
Authors: Asuka Hirai-Yuki; Jason K Whitmire; Michael Joyce; D Lorne Tyrrell; Stanley M Lemon Journal: Cold Spring Harb Perspect Med Date: 2019-01-02 Impact factor: 6.915
Authors: Christine Y L Tham; Janine Kah; Anthony T Tan; Tassilo Volz; Adeline Chia; Katja Giersch; Yvonne Ladiges; Alessandro Loglio; Marta Borghi; Camille Sureau; Pietro Lampertico; Marc Lütgehetmann; Maura Dandri; Antonio Bertoletti Journal: Cell Rep Med Date: 2020-07-21
Authors: Stephanie Jung; Tina von Thülen; Ines Yang; Viktoria Laukemper; Benjamin Rupf; Harshavardhan Janga; Georgios-Dimitrios Panagiotidis; Andreas Schoen; Marina Nicolai; Leon N Schulte; Hannah-Lena Obermann; Friedemann Weber; Andreas Kaufmann; Stefan Bauer Journal: Nucleic Acids Res Date: 2020-10-09 Impact factor: 16.971