Interferon stimulated immune profile changes in a humanized mouse model of HBV infection

Yaping Wang, Liliangzi Guo, Jingrong Shi, Jingyun Li, Yanling Wen, Guoming Gu, Jianping Cui, Chengqian Feng, Mengling Jiang, Qinghong Fan, Jingyan Tang, Sisi Chen, Jun Zhang, Xiaowen Zheng, Meifang Pan, Xinnian Li, Yanxia Sun, Zheng Zhang, Xian Li, Fengyu Hu, Liguo Zhang, Xiaoping Tang () and Feng Li ()
Additional contact information
Yaping Wang: Guangzhou Medical University
Liliangzi Guo: Guangzhou Medical University
Jingrong Shi: Guangzhou Medical University
Jingyun Li: Institute of Biophysics, Chinese Academy of Sciences
Yanling Wen: Southern University of Science and Technology
Guoming Gu: Guangzhou XY Biotechnology Co., Ltd
Jianping Cui: Guangzhou Medical University
Chengqian Feng: Guangzhou Medical University
Mengling Jiang: Guangzhou Medical University
Qinghong Fan: Guangzhou Medical University
Jingyan Tang: Guangzhou Medical University
Sisi Chen: Guangzhou Medical University
Jun Zhang: Guangzhou Medical University
Xiaowen Zheng: Guangzhou Medical University
Meifang Pan: Guangzhou Medical University
Xinnian Li: Guangzhou Forevergen Medical Laboratory
Yanxia Sun: Cytek (Shanghai) Biosciences Co, Ltd
Zheng Zhang: Southern University of Science and Technology
Xian Li: Guangzhou XY Biotechnology Co., Ltd
Fengyu Hu: Guangzhou Medical University
Liguo Zhang: Institute of Biophysics, Chinese Academy of Sciences
Xiaoping Tang: Guangzhou Medical University
Feng Li: Guangzhou Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg and/or young ages, is still unresolved due to the lack of surrogate models. Here, we generate a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrate that human IFN stimulates gene expression profiles in huIFNAR peripheral blood mononuclear cells (PBMCs) are similar to those in human PBMCs, supporting the representativeness of this mouse model for functionally analyzing human IFN in vivo. Next, we reveal the tissue-specific gene expression atlas across multiple organs in response to human IFN treatment; this pattern has not been reported in healthy humans in vivo. Finally, by using the AAV-HBV model, we test the antiviral effects of human interferon. Fifteen weeks of human PEG-IFNα2 treatment significantly reduces HBsAg and HBeAg and even achieves HBsAg seroconversion. We observe that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon may be critical for HBsAg suppression. Our huIFNAR mouse can authentically respond to human interferon stimulation, providing a platform to study interferon function in vivo. PEG-IFNα2 treatment successfully suppresses intrahepatic HBV replication and achieves HBsAg seroconversion.

Date: 2023
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DOI: 10.1038/s41467-023-43078-5

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