LAUSR

BACKGROUND AND AIMS Long-term maintenance of viral control, even HBsAg loss, remains a challenge for chronic hepatitis B (CHB) patients undergoing nucleos(t)ide analogue (NA) discontinuation. This study aimed to investigate the relationship between HBV-specific T cell responses targeting peptides spanning the whole proteome and clinical outcomes in CHB patients after NA discontinuation. APPROACH AND RESULTS Eighty-eight CHB patients undergoing NA discontinuation were classified as responders (remained relapse-free up to 96 wk) or relapsers (relapsed patients who underwent NA re-treatment for up to 48 weeks and re-achieved stable viral control). HBV-specific T cell responses were detected at baseline and longitudinally throughout follow-up. We found responders had a greater magnitude of HBV Polymerase (Pol)-specific T cell responses than relapsers at baseline. After long-term NA discontinuation, simultaneously enhanced HBV Core- and Pol-induced responses were observed in responders. Particularly, responders with HBsAg loss possessed enhanced HBV Envelope (Env)-induced responses after short and long-term follow-up. Notably, CD4+T cells accounted for the predominance of HBV-specific T cell responses. Correspondingly, CD4-deficient mice showed attenuated HBV-specific CD8+T cell responses, reduced HBsAb-producing B cells, and delayed HBsAg loss; in contrast, in vitro addition of CD4+T cells promoted HBsAb production by B cells . Additionally, interleukin (IL)-9, rather than PD-1 blockade, enhanced HBV Pol-specific CD4+T cell responses. CONCLUSION HBV-specific CD4+T cell responses induced by the targeted peptide possess specificities for long-term viral control and HBsAg loss in CHB patients undergoing NA discontinuation, indicating that CD4+T cells specific for distinct HBV antigens may endow with divergent antiviral potential.