Usai, C. (Carla)

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    Animal models of chronic hepatitis delta virus infection host–virus immunologic interactions
    (MDPI, 2015) González-Aseguinolaza, G. (Gloria); Suarez-Amaran, L. (Lester); Usai, C. (Carla); Aldabe, R. (Rafael)
    Hepatitis delta virus (HDV) is a defective RNA virus that has an absolute requirement for a virus belonging to the hepadnaviridae family like hepatitis B virus (HBV) for its replication and formation of new virions. HDV infection is usually associated with a worsening of HBV-induced liver pathogenesis, which leads to more frequent cirrhosis, increased risk of hepatocellular carcinoma (HCC), and fulminant hepatitis. Importantly, no selective therapies are available for HDV infection. The mainstay of treatment for HDV infection is pegylated interferon alpha; however, response rates to this therapy are poor. A better knowledge of HDV–host cell interaction will help with the identification of novel therapeutic targets, which are urgently needed. Animal models like hepadnavirus-infected chimpanzees or the eastern woodchuck have been of great value for the characterization of HDV chronic infection. Recently, more practical animal models in which to perform a deeper study of host virus interactions and to evaluate new therapeutic strategies have been developed. Therefore, the main focus of this review is to discuss the current knowledge about HDV host interactions obtained from cell culture and animal models.
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    Characterization of a mouse model for the study of hepatitis delta virus infection
    (2018-10-30) Usai, C. (Carla); González-Aseguinolaza, G. (Gloria); Aldabe, R. (Rafael)
    Hepatitis delta virus (HDV) is a defective RNA virus that depends on hepatitis B virus (HBV) for the formation of new virions. HDV induces the most severe form of human viral hepatitis with the worst prognosis. However, the specific reasons for the severity of the disease remain unknown. Studying hepatitis delta virus (HDV) and developing new treatments is hampered by the absence of small animal models. Here we describe a robust mouse model of HDV infection that mimics several important characteristics of the human disease. HDV- and HBV-replication competent genomes were delivered to the mouse liver using adeno-associated viruses (AAV) (AAV-HDV and AAVHBV). 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-regulation of genes involved in the development of liver pathologies. HDV replication induced a sustained type-I IFN response, which was significantly ameliorated 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. A significant liver inflammatory infiltrate were observed in immunocompetent as well in partially immunodeficient strais. Activated T lymphocytes, natural killer cells, dendritic cells and pro-inflammatory macrophages account for the majority of the inflammatory infiltrate and contribute in the hepatic expression of TGF-β, ISG15, ADAR-1, IP10, PKR, and USP18. However, neither T cells, natural killer cells nor macrophages are necessary for the induction of the observed liver damage; on the contrary, our data indicate that macrophages have a protective role early after infection. The role of type I- and type II IFN was also discarded. Moreover, we found that the hepatic expression of the HDV antigens in the absence of active HDV replication is sufficient to induce a dose-dependent liver toxicity.