Antiviral and immune modulatory activities of STING agonists in a mouse model of persistent hepatitis B virus infection.

Activation of antiviral immune responses against hepatitis B virus (HBV) is essential for the durable control of chronic HBV infection and the functional cure of chronic hepatitis B. As a molecular hub at the interface of innate and adaptive immunity, the stimulator of interferon (IFN) genes (STING) is well suited as a therapeutic target to break the immune tolerance against chronic viral infections and tumors. Using STING knockout and human STING knock-in mouse models, we first demonstrated that STING agonist treatment activated robust innate immune responses in the spleen and liver and efficiently suppressed HBV DNA replication in the livers of AAV-HBV transduced mice in a STING-dependent manner. We further demonstrate that AAV-HBV transduced mice are well tolerated for the long-term treatment of STING agonist diamidobenzimidazole (diABZI) at the optimized dose and dosing schedules. Virological and hepatic bulk and single-cell RNA-seq analyses revealed that diABZI treatment activated immune responses in liver microenvironment and significantly inhibited HBV replication and HBeAg expression. Antibodies against HBV surface antigen (HBsAg), HBs-Ab, became detectable in 1/4 mice after 5 weeks of treatment. In conclusion, our findings imply that diABZI treatment activates a STING-dependent immune response that controls HBV replication in a mouse model of persistent HBV infection and thus establishes a scientific basis for further development of STING agonists as immune therapeutics for the treatment of chronic hepatitis B.