Comparative analysis of human, rodent and snake deltavirus replication

The recent discovery of Hepatitis D (HDV)-like viruses across a wide range of taxa led to the establishment of the Kolmioviridae family. Recent studies suggest that kolmiovirids can be satellites of viruses other than Hepatitis B virus (HBV), challenging the strict HBV/HDV-association dogma. Studying whether kolmiovirids are able to replicate in any animal cell they enter is essential to assess their zoonotic potential. Here, we compared replication of three kolmiovirids: HDV, rodent (RDeV) and snake (SDeV) deltavirus in vitro and in vivo. We show that SDeV has the narrowest and RDeV the broadest host cell range. High resolution imaging of cells persistently replicating these viruses revealed nuclear viral hubs with a peculiar RNA-protein organization. Finally, in vivo hydrodynamic delivery of viral replicons showed that both HDV and RDeV, but not SDeV, efficiently replicate in mouse liver, forming massive nuclear viral hubs. Our comparative analysis lays the foundation for the discovery of specific host factors controlling Kolmioviridae host-shifting. Hepatitis D viruses (HDV) is a human pathogen responsible for severe liver disease. Although it was the only known member of its family for over 40 years, recent studies have discovered related viruses in a variety of animal hosts. To assess the potential of these newly discovered viruses to infect humans and animals distinct from their known hosts, we compare the replication of HDV, rodent (RDeV) and snake (SDeV) deltaviruses through various methods in cell culture and in a mouse model. We describe common and divergent features of these three viruses, showing that RDeV has a broad host range whereas SDeV does not. Finally, we describe RDeV replication in vivo for the first time. Our study paves the way for understanding the lifecycle of these newly discovered enigmatic satellite viruses.