Efficient hepatitis delta virus RNA replication in avian cells requires a permissive factor(s) from mammalian cells

Hepatitis delta virus (HDV) is a highly pathogenic human RNA virus whose ge nome is structurally related to those of plant viroids. Although its spread from cell to cell requires helper functions supplied by hepatitis B virus (HBV), intracellular HDV RNA replication can proceed in the absence of HBV proteins. As HDV encodes no RNA-dependent RNA polymerase, the identity of t he (presumably cellular) enzyme responsible for this reaction remains unkno wn. Here Nye show that, in contrast to mammalian cells, avian cells do not support efficient HDV RNA replication and that this defect cannot be rescue d by provision of HDV gene products in trans. Contrary to earlier assertion s, this defect is not due to enhanced apoptosis triggered in avian cells by HDV. Fusion of avian cells to mammalian cells rescues HDV replication in a vian nuclei, indicating that the nonpermissive phenotype of avian cells is not due to the presence of dominantly acting inhibitors of replication. Rat her, avian cells lack one or more essential permissive factors present in m ammalian cells. These results set the stage for the identification of such factors and also explain the failure of earlier efforts to transmit HDV inf ection to avian hosts harboring indigenous hepadnaviruses.