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

Liver Int. 2021 Dec;41(12):2866-2873. doi: 10.1111/liv.15033. Epub 2021 Aug 29.

Abstract

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)α treatment course. However, severe side effects may hamper the use of IFNα in immunocompromised transplant recipient patients. IFNλ 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 pegIFNλ 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 IFNλ receptor (IFNLR1) and are responsive to pegIFNλ. Treatment with pegIFNλ of liver-humanized mice persistently infected with HEV genotype 3 showed that pegIFNλ was well tolerated. Dose escalation studies showed that although HEV was not cleared at pegIFNλ doses up to 0.12 mg/kg for a maximum of 8 weeks, a dose of 0.3 mg/kg pegIFNλ treatment resulted in complete clearance of HEV antigen and HEV RNA from the liver in 8 out of 9 liver-humanized mice.

Conclusions: PegIFNλ is well tolerated in mice and leads to clearance of a persistent HEV infection in liver-humanized mice.

Keywords: cytokines; hepatitis E virus; interferon alpha; interferon lambda; viral hepatitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / therapeutic use
  • Hepatitis E virus* / genetics
  • Hepatitis E*
  • Humans
  • Interferon-alpha / pharmacology
  • Interferon-alpha / therapeutic use
  • Mice
  • Receptors, Interferon / therapeutic use

Substances

  • Antiviral Agents
  • IFNLR1 protein, mouse
  • Interferon-alpha
  • Receptors, Interferon