Co-Circulation of Divergent Strains Supports Vector-Mediated Transmission of Rodent Hepacivirus J (Orthohepacivirus glareoli)

Orthohepacivirus glareoli (RHVJ, Hepaciviridae) and its natural host, the bank vole (Myodes glareolus), have been proposed as a model system for human hepatitis C research, yet the mode of transmission remains largely unknown. Here, we investigated spatial patterns of RHVJ sequence diversity and evolutionary relationships using novel sequences from dense regional sampling alongside all published NS3 gene sequences. Phylogenetic analyses revealed mostly local clustering of RHVJ sequences, resulting in isolation-by-distance patterns at regional geographic scales. This suggests primarily local transmission of the virus. However, nucleotide sequence divergence of up to 19% within bank vole populations is difficult to reconcile with local transmission of RHVJ alone, implying that mechanisms beyond local evolution shape the extensive sequence diversity of RHVJ at local scales. Using spatially explicit computer simulations of sequence evolution, we contrasted the phylogenetic relationships resulting from exclusively short-distance transmission, e.g., from vole to vole, with those resulting when rare long-distance transmission events were included. The latter produced phylogenetic patterns comparable to those of RHVJ, including monophyletic clustering of samples from distant locations and unresolved basal nodes. We suggest that the transmission of RHVJ likely involves at least occasionally a vector, as the mobility of its natural rodent host is strongly limited.