Functional immune responses induced by a capsid assembly modulator in chronic hepatitis B virus-infected humanized mice

Current treatment strategies for hepatitis B virus (HBV) are lifelong and rarely curative. Finite therapeutic strategies aim to restore efficient immune responses in chronically infected patients for functional cures. Here, we investigate the impact of treatment with the capsid assembly modulator (CAM) GLP-26 in an immunocompetent humanized mouse model of chronic HBV. GLP-26 treatment clears viremia and HBV surface antigen (HBsAg), reduces hepatitis, and potentiates anti-HBs antibody (HBsAb) development. Remarkably, after discontinuing GLP-26, either viral control or viral rebound occurs in half the cohort. In particular, the viral controllers display seroconversion (HBsAg-/HBsAb+) and development of neutralizing antibodies. In the liver, cytotoxic natural killer cells and activated memory T cells are enriched, including HBV-specific polyfunctional T cell responses. Thus, finite treatment with a potent antiviral CAM results in viral clearance and antigen depletion, enabling effective adaptive immune responses and viral control off therapy, suggestive of a functional cure.