Molecular movie of Hantaan virus genome replication by its viral polymerase revealed using high-resolution cryo-electron microscopy

The order Bunyavirales includes a large number of viruses that have a segmented negative-stranded RNA genome (sNSV). Divided into 12 families, some Bunyaviruses are major human pathogens, such as Lassa virus and Crimean Congo virus. Other viruses are emerging, such as Hantaviruses, which mainly infect arthropods and rodents, but can also infect humans, causing encephalitis or haemorrhagic fevers. There are currently no drugs or vaccines available to counter these viruses.
In this context, researchers from Methods and Electron Microscopy Group are interested in the Hantaan virus (HTNV) and more specifically its polymerase. This central enzyme carries out viral replication, which consists in the production of complete copies of genome segments. Their aim is to understand the molecular mechanisms involved in replication. To this end, they have characterized the conditions of activity in vitro, enabling us to block the polymerase at various key stages of replication. They have then determined high-resolution 3D structures of each of these steps using cryo-electron microscopy using the Glacios cryo-electron microscope (IBS electron microscopy platform). The visualization of the different viral RNAs in these structures and the analysis of the polymerase conformational changes reveal with near-atomic precision how the genome is duplicated. In addition, they also observed an inactive polymerase conformation never seen before in any Bunyavirus, highlighting important reconfigurations of the polymerase active site required for polymerase activation. This represents an important advance not only from a fundamental point of view, but also for the future development of anti-viral capable of blocking viral replication.

Structures of active Hantaan virus polymerase uncover the mechanisms of Hantaviridae genome replication. Durieux Trouilleton Q, Barata-Garcia S, Arragain B, Reguera J, Malet H. Nature Communications 2023 ;14(1):2954

Contact : Hélène Malet (IBS/Methods and Electron Microscopy Group)