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Hepatitis D virus interferes with hepatitis B virus RNA production via interferon-dependent and -independent mechanisms

Published:January 23, 2023DOI:https://doi.org/10.1016/j.jhep.2023.01.005

      Highlights

      • we define the HDV-induced signature transcriptomic modulations mainly composed of ISGs
      • ISGs are upregulated upon HDV infection but not in cells only expressing HDAg alone
      • HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms
      • HDV infection and HDAg expression decrease the levels of nascent HBV RNAs and accelerated the decay of HBV RNA
      • HDAg are associated with HBV RNAs

      Abstract

      Background & Aims

      Chronic co-infection with hepatitis B and D viruses (HBV and HDV) leads to the most aggressive form of chronic viral hepatitis. Here, we aimed at elucidating the molecular mechanisms leading to the interference of HDV on HBV observed in most co-infected patients.

      Methods

      Patient liver tissues, primary human hepatocytes, HepaRG cells and human liver chimeric mice were used to analyze the effect of HDV on HBV using virological and RNA-seq analyses, as well as RNA synthesis, stability and association assays.

      Results

      Transcriptomic analyses in cell culture and mouse models of co-infection allowed to define the HDV-induced signature mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in HDV-HBV chronically infected patients but not in cells only expressing the HDV antigens (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNAs synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNAs and HDAg are associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as hepatitis C virus (HCV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

      Conclusions

      Our data indicate that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms. Specifically, we uncover a new viral interference mechanism in which proteins of a satellite virus affect RNA production of its helper virus. Exploiting these finding could pave the way to the development of new therapeutic strategies against HBV.

      Impact and implications

      Although, the molecular mechanisms remained unexplored, it was known for long that despite its dependency, HDV decreased HBV viremia in patients. Here, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNAs metabolism and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way to the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNAs and the HDV-induced modulation signature may allow to the draw correlation withthe responsiveness to IFN alpha treatment and thereby ultimately help in the management of HBV/HDV co-infected patients.

      Graphical abstract

      KeyWords

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