Disparate tetraparvovirus species linked to hepatitis.

The role of human tetraparvoviruses (PARV4) in cases of acute illness is poorly characterized, and the contribution of animal-associated tetraparvoviruses to human disease is unknown. In this study, we applied metagenomic and viral-enrichment next-generation sequencing to plasma from patients with diagnostically unresolved acute illness in Georgia (non-A-C hepatitis) and Bangladesh (acute febrile illness), and two tetraparvovirus genomes were recovered. Specimen HEP004 from a Georgian patient with acute hepatitis contained a virus clustering within Tetraparvovirus ungulate4, a species associated with sheep and goats, representing the first detection of this species in human plasma. Specimen 39HEP0432 from a Bangladeshi patient with fever and jaundice contained a human PARV4 grouping within a clade of genotype 2 previously reported in pediatric acute encephalitis cases in South Asia. Within-host minor variation was detected in both genomes, raising the possibility of ongoing replication. Phylogenetic and ancestral sequence analyses of human PARV4 genotype 2 identified lineage-defining capsid amino acid substitutions in the South Asian clade (which 39HEP0432 shared), situated in surface-exposed positions that may influence viral tropism or host immune interactions. These findings expand the known diversity of tetraparvoviruses detected in humans, including an ungulate-associated species with possible zoonotic potential, and provide sequence data to support targeted screening in cases of unexplained hepatitis and febrile illness.