Functional anti-preS1 antibody responses associated with viral control in chronic hepatitis B

BACKGROUND: The preS1 region of the HBV large surface protein binds sodium taurocholate cotransporting polypeptide (NTCP) to mediate viral entry, but the serological and functional relevance of circulating preS1 antigen and anti-preS1 antibodies in chronic hepatitis B (CHB) is not well defined. OBJECTIVE: To characterise serum preS1 antigen and anti-preS1 IgG across CHB and evaluate their virological and functional significance. DESIGN: ELISAs for preS1 antigen and anti-preS1 IgG were developed and applied to 549 individuals with chronic HBV infection, 107 individuals with functional cureand 110 vaccinated healthy controls. Neutralising activity was assessed using HBV and hepatitis D virus (HDV) infection models, preS1-NTCP competitive assays and peptide microarrays. Baseline anti-preS1 IgG was evaluated in 51 patients discontinuing nucleos(t)ide analogue (NUC) therapy. RESULTS: PreS1 antigen was highest in hepatitis B e antigen (HBeAg)-positive patients and correlated with HBV DNA, hepatitis B surface antigen and HBeAg. Anti-preS1 IgG was detectable across disease phases, inversely associated with HBV DNA, positively correlated with alanine aminotransferase/aspartate aminotransferase and remained detectable in some individuals with functional cure. Sera with low preS1 and high anti-preS1 IgG showed potent HBV/HDV neutralising activity by inhibiting viral entry and blocking preS1-NTCP binding. Dominant linear epitopes mapped to preS1 regions involved in NTCP binding. High baseline anti-preS1 IgG was associated with sustained virological suppression after NUC withdrawal. CONCLUSION: PreS1 antigenaemia and anti-preS1 IgG exhibit distinct serological patterns linked to HBV replication and endogenous viral control. High anti-preS1 IgG confers potential neutralising activity and associates with sustained off-therapy suppression, highlighting its functional relevance as an indicator of host viral control.