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

作者：Wang, Yaping; Guo, Liliangzi; Shi, Jingrong; Li, Jingyun; Wen, Yanling; Gu, Guoming; Cui, Jianping; Feng, Chengqian; Jiang, Mengling; Fan, Qinghong; Tang, Jingyan; Chen, Sisi; Zhang, Jun; Zheng, Xiaowen; Pan, Meifang; Li, Xinnian; Sun, Yanxia; Zhang, Zheng; Li, Xian; Hu, Fengyu; Zhang, Liguo; Tang, Xiaoping^*; Li, Feng^*

来源：Nature Communications, 2023, 14(1): 7393.

DOI：10.1038/s41467-023-43078-5

• HEPATITIS-B-VIRUS
• CELL-CULTURE
• HEPATOCELLULAR-CARCINOMA
• SUSCEPTIBILITY
• PACKAGE

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-IFN alpha 2 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-IFN alpha 2 treatment successfully suppresses intrahepatic HBV replication and achieves HBsAg seroconversion. @@@ There is increasing evidence that treatment of hepatitis B with interferon alpha can be beneficial. Here, Wang et al, present a type 1 interferon receptor humanized mouse model and characterize it as a platform in which to study interferon function in vivo.

• 单位
  中国科学院; 广州医学院; 6; 1