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Hepatitis B virus evades immune recognition via RNA adenosine deaminase ADAR1-mediated viral RNA editing in hepatocytes

Abstract

HBV is considered as a “stealth” virus that does not invoke interferon (IFN) responses; however, the mechanisms by which HBV bypasses innate immune recognition are poorly understood. In this study, we identified adenosine deaminases acting on RNA 1 (ADAR1), which is a key factor in HBV evasion from IFN responses in hepatocytes. Mechanically, ADAR1 interacted with HBV RNAs and deaminated adenosine (A) to generate inosine (I), which disrupted host immune recognition and thus promoted HBV replication. Loss of ADAR1 or its deficient deaminase activity promoted IFN responses and inhibited HBV replication in hepatocytes, and blocking the IFN signaling pathways released the inhibition of HBV replication caused by ADAR1 deficiency. Notably, the HBV X protein (HBx) transcriptionally promoted ADAR1 expression to increase the threshold required to trigger intrinsic immune activation, which in turn enhanced HBV escape from immune recognition, leading to persistent infection. Supplementation with 8-azaadenosine, an ADAR1 inhibitor, efficiently enhanced liver immune activation to promote HBV clearance in vivo and in vitro. Taken together, our results delineate a molecular mechanism by which HBx promotes ADAR1-derived HBV immune escape and suggest a targeted therapeutic intervention for HBV infection.

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Acknowledgements

Immunofluorescence images were taken and flow cytometry data were analyzed at the Advanced Medical Research Institute, Shandong University. The authors thank Professor Haizhen Zhu (Hunan University) for the gift of the HLCZ-01 cell line. This work was supported by grants from the National Science Foundation of China (Key program 81830017, Nos. 81672425 and 81902051), the National Natural Science Fund for Outstanding Youth Fund (81425012), Taishan Scholarship (No. tspd20181201), Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy in Universities of Shandong, Key Research and Development Program of Shandong (2019GSF108238), the National Key Research and Development Program (2018YFE0126500 and 2016YFE0127000), China Mobility Grant jointly funded by the National Science Foundation of China and the Swedish Foundation for International Cooperation in Research and Higher Education (STINT), and China Postdoctoral Science Foundation (No. 2018 M30782).

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Contributions

LW and ZCW carried out most of the experiments and analyzed data. YS contributed to the establishment of the protocols for the RIP and RNA pull-down assays. YS, ZHW, YZ, XP, XZ, and CL participated in the in vivo experiments. YKZ was involved with the IHC assay. CG provided help in the IFN pathway analysis. XL, NL, and LG were involved in the study design and manuscript preparation. LW wrote the manuscript with the help of CM. Author CM was in charge of the study design, work organization/supervision, and manuscript review. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Zhuanchang Wu or Chunhong Ma.

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The authors declare no competing interests.

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Wang, L., Sun, Y., Song, X. et al. Hepatitis B virus evades immune recognition via RNA adenosine deaminase ADAR1-mediated viral RNA editing in hepatocytes. Cell Mol Immunol 18, 1871–1882 (2021). https://doi.org/10.1038/s41423-021-00729-1

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Keywords

  • ADAR1
  • RNA editing
  • IFN response
  • HBV replication
  • HBx

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