Comprehensive immune profile changes to human interferon stimulation in normal and HBV-infected conditions in a humanized mouse I

The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg or/and young ages, is still unresolved for lacking surrogate models. Here, we generated a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrated that human IFN stimulated a similar gene expression profile of huIFNAR peripheral blood mononuclear cells (PBMC) to what in human PBMCs, supporting the representativeness of the novel mouse model in functionally analyzing human IFN in vivo. Next, we revealed a markedly tissue-specific gene expression atlas against human IFN treatment in the multiple organs less appreciated in healthy humans in vivo. Finally, using the AAV-HBV model, we test the antiviral effects of human interferon in this mouse. Fifteen-week human PEG-IFNa2 treatment significantly reduced HBsAg and HBeAg and even achieved HBsAg seroconversion. We observed that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon might be critical for HBsAg suppression. In conclusion, our novel huIFNAR mouse can authentically respond to human Interferon stimulation, providing a novel platform to study interferon function in vivo. The PEG-IFNa2 treatment successfully suppresses intrahepatic HBV replication and achieved HBsAg seroconversion in some mice. Overall design: In an effort to explore the mechanism underlying the functional cure of Hepatitis B Virus (HBV) by interferon (IFN), we developed a humanized mouse model expressing the type I interferon receptor (huIFNAR mouse) via a CRISPR/Cas9-based knock-in technique. Further, we unveiled a remarkably tissue-specific gene expression atlas in response to human IFN treatment across several organs; these findings highlight the potential underappreciated effects of IFN in healthy human tissues in vivo, thereby expanding the scope of our understanding of IFN action.