Unveiling the Molecular Architecture of HBV Spherical Subviral Particles: Structure, Symmetry, and Lipid Dynamics.

Since the discovery of the Australia antigen, now known as the hepatitis B surface antigen (HBsAg), significant research has been conducted to elucidate its physical, chemical, structural, and functional properties. Subviral particles (SVPs) containing HBsAg are highly immunogenic, non-infectious entities that have not only revolutionized vaccine development but also provided critical insights into HBV immune evasion and viral assembly. Recent advances in cryo-electron microscopy (cryo-EM) have uncovered the heterogeneity and dynamic nature of spherical HBV SVPs, emphasizing the essential role of lipid-protein interactions in maintaining particle stability. In this review, recent progress in understanding the molecular architecture of HBV SVPs is consolidated, focusing on their symmetry, lipid organization, and disassembly-reassembly dynamics. High-resolution structural models reveal unique lipid arrangements that stabilize hydrophobic residues, preserve antigenicity, and contribute to SVP functionality. These findings highlight the significance of hydrophobic interactions and lipid-protein dynamics in HBV SVP assembly and stability, offering valuable perspectives for optimizing SVP-based vaccine platforms and therapeutic strategies.