Interferon-γ-associated responses to woodchuck hepatitis virus infection in neonatal woodchucks and virus-infected hepatocytes

Acute hepatitis and recovery from woodchuck hepatitis virus (WHV) infection involves increased intrahepatic expression of interferon‐gamma (IFN‐γ) and tumour necrosis factor‐alpha (TNF‐α) mRNAs. In the present study, recovery correlated with increased intrahepatic expression of mRNAs for major histocompatibility complex class 1 (MHC1), β2‐microglobulin, 2′5′‐oligoadenylate synthetase (2′5′‐OAS), and indoleamine dioxygenase (IDO). By comparison, acute WHV infection progressing to chronicity was associated with diminished expression of these IFN‐γ‐associated mRNAs in liver. Transfection of WHV‐infected primary hepatocytes (WPH) from WHV carriers with an IFN‐γ‐expressing plasmid (pIFN‐γ) resulted in dose‐dependent accumulations of MHC1, TNF‐α, 2′5′‐OAS, and IDO mRNAs within 96 h. Markers of T cells and immune‐mediated cytotoxicity that accumulate in recovering liver were not apparent in WPH based on the relative lack of CD3, CD4, Fas ligand, perforin, and granzyme B mRNAs. Expression of pIFN‐γ, and TNF‐α‐expressing plasmid (pTNF‐α), did not affect total WHV RNA, or fully double‐stranded WHV DNA in WPH, but each reduced some of the replicative intermediate (RI) species of WHV DNA synthesis. WPH treated with recombinant IFN‐α protein had a higher fold induction of 2′5′‐OAS mRNA associated with partial reductions in WHV RNAs and the major RI species. Thus, IFN‐γ expression in carrier WPH induced several host responses often observed in liver of recovering woodchucks, and impaired a stage of WHV DNA synthesis by a non‐cytolytic mechanism mediated by TNF‐α. Local enhancement of IFN‐γ‐associated responses in chronic WHV‐infected hepatocytes may promote therapeutic antiviral effects, but additional effector mechanisms evident during recovery appear necessary for more complete clearance of WHV infection.