Deleterious effects of hepatitis delta virus replication on host cell proliferation

Hepatitis delta virus (HDV) infection and spread in vivo are dependent upon coinfection by hepatitis B virus (HBV), and dual HDV/HBV infection is freq uently more severe than HBV infection alone, raising the possibility that H DV infection may be deleterious to cells. Here we have examined the effects of HDV replication on the long-term growth of cultured cells, Our results show that most cells transfected with HDV cDNA do not give rise to stable c ell lines expressing viral antigens or replicative intermediates; in additi on, cotransfection of HDV replicons with a plasmid vector expressing a hygr omycin resistance marker results in a dose-dependent impairment of hygromyc in-resistant colony formation. When cells transfected with replication-comp etent HDV cDNA are followed prospectively, a progressive decline in viral R NA replication and a steady decrease in the proportion of cells expressing delta antigen are observed. However, in transient transfection assays, no e vidence was found to link HDV replication to apoptosis or to cell cycle arr est, nor did HDV replication confer on host cells enhanced sensitivity to i nducers of apoptosis, Thus, HDV replication does not appear to be acutely c ytotoxic, However, in dividing cells HDV replication is associated with a s ubtler growth disadvantage, leading to selection in culture for cells displ aying diminished HDV expression. This effect would not be expected to cause hepatitis in vivo but might contribute to impaired liver regeneration in t he setting of ongoing hepatocellular injury.