Background & aims: Current treatments of chronic hepatitis B are rarely curative. Capsid assembly modulators (CAMs) target capsid formation by the hepatitis B virus (HBV) core protein. Class A CAMs (CAM-A) induce abnormal core protein assembly but how they affect core protein dynamics and inhibit HBV replication is only partially understood.
Methods: Human liver chimeric mice and HBV-susceptible cells were infected to monitor dynamic changes and the fate of core protein and assembled capsids. We analyzed HBV virus and protein dynamics over four weeks under treatment of CAM-A molecule HAP_R01.
Results: We found an altered nuclear-cytoplasmic distribution of HBV core protein upon treatment with HAP_R01. This effect was confirmed in primary human hepatocytes and in HBV-infected liver-humanized mice. Mechanism-of-action studies in HBV-permissive cells demonstrated that HAP_R01 primarily targets newly synthesized core protein and affects capsid assembly, core protein localization and solubility in a dose- and time-dependent manner. At 50 nM, HAP_R01 promoted assembly of HBV genome-free capsids and nuclear accumulation of core protein. At ≥500 nM, HAP_R01 treatment reduced soluble core protein and capsid levels, but markedly increased insoluble core protein levels, resulting in an overall intracellular accumulation of core protein. Insoluble nuclear agglomerations of core protein were deposited in promyelocytic leukemia nuclear bodies. Treating infected cells for 31 days significantly reduced an established covalently closed circular (ccc)DNA pool and secreted HBsAg and HBeAg levels, by inhibiting cccDNA replenishment.
Conclusions: As an exemplary CAM-A, HAP_R01 inhibits HBV genome replication by perturbing capsid assembly and by inducing insoluble core protein accumulation in the nucleus that affects replenishment of the cccDNA pool
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