Chronic HBV infection impairs induction of interferon responsive genes in human hepatocytes repopulating the liver of uPA/SCID mice

Chronic hepatitis B virus (HBV) infection is characterized by dysfunctional innate and adaptive immune responses and recent in vitro studies indicated that the interferon (IFN) signaling is impaired in HBV-transfected hepatoma cell lines. Aim of this study was to investigate whether HBV can directly interfere with the hepatocellular IFN alpha response in chronically infected human hepatocytes repopulating the livers of uPA/SCID mice. Methods: Using primers specific for human transcripts and not cross-reacting with murine genes, we comparatively analysed responsiveness of transplanted hepatocytes to treatment with human IFN alpha (1350 IU/g daily) both in uninfected and in HBV-chronically infected (median viremia 3×10⁷ copies/ml) chimeric mice transplanted with human hepatocytes isolated from the same liver donor. To determine kinetics of induction of human IFN responsive genes (IRGs), animals treated either with IFN or PBS were sacrificed at 4, 8 or 24h after the last injection, respectively. Results: Five days of IFN alpha administration induced moderate reduction of HBV-DNA serum titres (median 0.75 log), rcDNA and pgRNA amounts compared to untreated control animals, demonstrating a direct antiviral effect of IFN alpha in human hepatocytes. As expected, IFN treatment induced significant up-regulation of human OAS or MxA RNA levels in uninfected chimeric animals (median 3-fold OAS and 10-fold MXA, 8 hr after injection). However, we found that induction of the same RNA transcripts was clearly impaired in the livers of IFN-treated HBV-infected mice. Similarly, IFN treatment was able to increase Myd88 and TLRs RNA levels in uninfected human hepatocytes, while in HBV-infected hepatocytes expression levels remained unchanged. Conclusions: These results provide direct evidence that HBV can specifically hinder the cellular response to IFN in chronically infected human hepatocytes by interfering with the activation of several genes of the innate immune system.

HBV - IFN - innate immunity - uPA mice