Treatment induced clearance of hepatitis E viruses by interferon-lambda in liver-humanized mice

Background Hepatitis E viruses (HEV) are an underestimated global cause of enterically transmitted viral hepatitis, which may persist in immunocompromised hosts, posing a risk for progressive liver fibrosis with limited treatment options. We previously established liver-humanized mice as a model for chronic HEV infections, which can be cleared by a 2-week pegylated (peg)-Interferon(IFN)alpha treatment course. However, severe side effects may hamper the use of IFN alpha in immunocompromised transplant recipient patients. IFN lambda may be a valuable alternative, as its receptor is less ubiquitously expressed. Aims In this study, we assess the in vitro and in vivo potency of pegIFN lambda to induce innate immune signalling in liver cells and to clear a persistent HEV infection in liver-humanized mice. Methods & Results We found that human liver cells expressed the IFN lambda receptor (IFNLR1) and are responsive to pegIFN lambda. Treatment with pegIFN lambda of liver-humanized mice persistently infected with HEV genotype 3 showed that pegIFN lambda was well tolerated. Dose escalation studies showed that although HEV was not cleared at pegIFN lambda doses up to 0.12 mg/kg for a maximum of 8 weeks, a dose of 0.3 mg/kg pegIFN lambda treatment resulted in complete clearance of HEV antigen and HEV RNA from the liver in 8 out of 9 liver-humanized mice. Conclusions PegIFN lambda is well tolerated in mice and leads to clearance of a persistent HEV infection in liver-humanized mice.