The Orthohantavirus G_N/G_C Spikes: Molecular Determinants of Infection and Targets for Antiviral Immune Interventions

Orthohantaviruses are globally distributed, rodent-borne RNA viruses associated with severe and often lethal disease in humans. The documented person-to-person transmission of Andes virus, endemic in South America, underscores their pandemic potential, and yet no effective treatments are available, while vaccines exist only for Hantaan and Seoul viruses. Key targets for antiviral intervention are the tetrameric G_N/G_C spikes, which are displayed on the viral surface. Here we review current molecular and cellular insights into these spikes, focusing on their roles during the viral infection cycle, such as receptor-mediated cell entry, membrane fusion, viral assembly, and cell exit. We also examine recent advances in therapeutic antibody developments and identify structurally conserved immune hotspots linked with their possible inhibitory mechanism. Finally, we discuss progress in G_N/G_C-based vaccine research and clinical trials, highlighting key achievements and remaining challenges to overcome the public health threat posed by orthohantaviruses.