High-resolution in situ structures of hantavirus glycoprotein tetramers

# High-resolution in situ structures of hantavirus glycoprotein tetramers *Published: 2026 Apr 30* bioRxiv. 2025 Jun 18:2025.06.17.660152. doi: 10.1101/2025.06.17.660152. New World hantaviruses cause severe infections in humans. Previous structural studies have advanced our understanding of hantavirus glycoprotein architecture; however, the lack of high-resolution structures of the glycoprotein tetramer and its lattice organization has limited mechanistic insights into viral assembly and entry. Here, we leveraged a virus-like particle (VLP) system to establish a cryo-electron microscopy workflow for lattice-forming viral glycoproteins. This enabled the determination of a 2.35 Å resolution structure of the membrane-embedded Andes virus (ANDV) glycoprotein tetramer as well as the structures of dimers of tetramers and a complex with antibody ADI-65534. These structures reveal previously uncharacterized features of glycoprotein organization, stability, and pH sensing. The immunization of mice with self-amplifying replicon RNA (repRNA) encoding ANDV-VLPs elicited high levels of glycoprotein-binding antibodies but equivalent titers of neutralizing antibodies compared with the repRNA-encoded native ANDV glycoprotein complex. These findings advance our understanding of hantavirus glycoprotein assemblies, laying a foundation for structure-based vaccine design. DOI: 10.1016/j.cell.2026.01.030