Cryo-EM structure of native spherical subviral particles isolated from HBV carriers.

Hepatitis B virus (HBV) contains 3 types of particles, i.e., 22-nm-diameter spherical and tubular subviral particles (SVPs) and 44-nm-diameter Dane particles. The SVPs are non-infectious and present strong immunogenicity, while Dane particles are infectious. In this study, we isolated spherical SVPs from HBV carriers' sera and determined their 3D structure at the resolution of ∼30 Å by cryo-electron microscopy (cryo-EM) single-particle reconstruction. Our cryo-EM structure suggests that the native HBV spherical SVP is irregularly organized, where spike-like features are arranged in a crystalline-like pattern on the surface. Strikingly, the hepatitis B surface antigen (HBsAg) in the native spherical SVPs folds as protrusions on the surface, as those on the native tubular SVPs and Dane particles, but is largely different from that in the recombinant octahedral SVPs. These results suggest a universal folding shape of HBsAg on the native HBV viral and subviral particles.