GLS4 Induces the Interferon Signaling Pathway During Hepatitis B Virus (HBV) Infection

ABSTRACT The development of therapeutic strategies capable of achieving functional cure remains an unmet need in chronic hepatitis B management. Class A capsid assembly modulators (CAM‐As) emerge as a promising treatment option. CAM‐As not only directly disrupt the normal assembly of capsids, but some of which have also been reported to activate the innate immune response in animal models with unclear mechanisms. GLS4 is one of CAM‐As with great potential. In this study, we investigate its capacity to activate immune response both in vitro and in vivo, as well as the underlying mechanisms involved. GLS4 activates the RIG‐I‐mediated interferon signaling pathway in both HBV‐expressing hepatocellular carcinoma cell lines and HBV carrier mouse models, as indicated by RNA‐seq. Besides, combination treatment with GLS4 and ritonavir elevates the frequencies of both peripheral blood IFNγ + NK cells and liver‐resident IFNγ + CD8+ T cells in the pAAV/HBV1.2 hydrodynamic injection (HDI) model. In conclusion, our study reveals a previously unknown mechanism by which GLS4 activates the interferon signaling pathway in HBV‐expressing hepatocytes. Furthermore, GLS4 partially restores innate and adaptive immunity in vivo. This signifies a potentially effective strategy for achieving a functional cure for HBV infection.