Transduction of primary woodchuck hepatocytes from chronic WHV carriers with helper-dependent AdV encoding woodchuck IFNα (wIFNα) resulted in the reduction of WHV proteins expression in vitro [169] . In vivo studies on chronically WHV-infected woodchucks, demonstrated that a single injection of 1 × 10 12 vp of this vector into the liver's portal vein could inhibit WHV replication by 1 log up to 11 weeks after the treatment [163] . The same approach with helper-dependent AdV expressing woodchuck IFNγ (wIFNγ) did not show any antiviral effect, even though the transduction led to the production of biologically active interferon [163] . Another study combined intravenous delivery wIFNγ by recombinant adenoviral vector with nucleos(t)ide analogues therapy. Chronic WHV carriers were treated with clevudine and emtricitabine (FTC), together, for 8 weeks and after the initial drop in viral load one group of animals received additionally two i.v. injections of 3 × 10 10 PFU of Ad-IFNγ. Delivery of wIFNγ induced inflammation, caused by T cell infiltration, and increased hepatocyte turnover. However, this effect did not induce additional antiviral outcome in comparison clevudine/emtricitabine biotherapy alone [164] . Similarly, poor therapeutic effect was observed for gene therapy based on both wIFNγ and wTNFα. Intravenous injection of those recombinant adenoviruses during clevudine treatment led to decrease of replicative intermediates of WHV DNA in the liver, beyond what could be achieved by clevudine alone. Nevertheless, 6 weeks after injection there was no significant difference between the groups of WHV carriers receiving AdV expressing the cytokines or beta-galactosidase as a control [165] . The benefits of using the immunomodulatory genes in this study are difficult to assess, since it was reported that adenovirus infection alone is sufficient to transiently suppress the WHV replication in chronically infected woodchucks [170] . The lack of therapeutic effect by direct delivery of IFNγ is consistent with in vitro data obtained from persistentlyinfected woodchuck primary hepatocytes. Treatment of the cells with wIFNγ, even in the presence of wTNFα, was not able to inhibit the WHV replication. Moreover, high concentration of those cytokines resulted in the loss of the cells during the culture [171] . This observation underlines the cytotoxic effect of Th1 cytokines on the woodchuck hepatocytes. Rapid downregulation of the IFNγ expression, after transduction of the liver cells with viral vector, could be one of the mechanisms to protect the organism from the potential toxicity of this cytokine in vivo [163] . In addition, several reports indicates that the level of wIFNγ and wTNFα is higher in the liver of chronic WHV carriers in comparison to naïve animals [172, 173] . Therefore, continuous presence of inflammatory cytokines in the liver during the chronic WHV infection could result in hyporesponsiveness of hepatocytes to such a therapy.