PRETREATMENT OF HUMANIZED uPA/SCID MICE WITH INTERFERON ALPHA STRONGLY INHIBITS THE ESTABLISHMENT OF HBV INFECTION

Activation of innate host defenses including the interferon signaling is critical tocounteract viral infections. A better understanding of how IFN-a) can affect HBV inthe early phases of infection may provide new clues about the mechanisms of chronicinfection and also support the design of improved therapeutic approaches. Aim of thisstudy was to investigate whether pegylated interferon alpha (peg-IFN-a) treatmentcould hinder the establishment of HBV infection in vivo. Methods: Human liver chimericuPA/SCID mice received peg-IFN-a) (25 ng/gr, i.p., twice per week) one week beforeand 2 weeks post HBV infection (p.i.), while untreated mice with similar levels ofchimerism were infected in parallel. The effects of peg-IFN-a) on human hepatocytesand HBV infection were determined by qRT-PCR and immunohistochemistry. Results: One week of peg-IFN-a treatment strongly increased the expression of interferonstimulated genes (ISGs), such as OAS–1, MxA, HLA-I, confirming the induction ofinnate defense mechanisms in human hepatocytes prior to infection. Notably, viremiawas promptly detected 3 weeks p.i. in control mice (4/4), while treated mice (4/4)remain PCR negative. Although all treated mice finally became HBV-positive (1/4week 5 and 4/4 week 8 p.i.), IFN-treatment led to significant differences in medianviremia levels (≈60 fold), HBsAg (median <7 vs. 185 IU/ml, treated vs. controls)and intrahepatic viral loads (rcDNA, cccDNA). In line with the PCR data, very fewscattered human hepatocytes stained HBcAg positive in mice initially treated withIFN, while nearly all human cells appeared HBcAg-positive in control mice sacrificed8 week p.i. Conclusions: IFN-mediated induction of innate antiviral defenses in theearly phases of infection strongly restrained infection establishment and spreading ofHBV among human hepatocytes in vivo. Further studies will be needed to investigatewhich step of the infection is mostly affected by therapeutically applied peg-IFN-a.

HBV - Peg-IFN - uPA/SCID