Interferon-alpha treatment rapidly clears Hepatitis E virus infection in humanized mice

Martijn D B Van De Garde,Lucio Gama,Gertine W Van Oord,Andre Boonstra,Robert A De Man,Thomas Vanwolleghem,Suzan D Pas,Youkyung Choi

doi:10.1038/s41598-017-07434-y

Abstract

Antiviral treatment options for chronic Hepatitis E Virus (HEV) infections are limited and immunological determinants of viral persistence remain largely unexplored. We studied the antiviral potency of pegylated interferon-α (pegIFNα) against HEV infections in humanized mice and modelled intrahepatic interferon stimulated gene (ISG) responses. Human gene expression levels in humanized mouse livers were analyzed by qPCR and Nanostring. Human CXCL10 was measured in mouse serum. HEV genotype 3 (gt3) infections were cleared from liver and feces within 8 pegIFNα doses in all mice and relapsed after a single pegIFNα injection in only half of treated animals. Rapid viral clearance by pegIFNα was confirmed in HEV gt1, but not in Hepatitis B Virus infected animals. No ISG induction was observed in untreated HEV gt3 and gt1 infected humanized livers compared to control chimeric mice, irrespective of the human hepatocyte donor, viral isolate or HEV infection duration. Human specific ISG transcript levels in mouse liver increased significantly after pegIFNα treatment and induced high circulating human CXCL10 in mouse serum. In conclusion, HEV gt1 and gt3 infections do not elicit innate intrahepatic immune responses and remain highly sensitive to pegIFNα in immunocompromised humanized mice.

Highlights

Hepatitis E Virus (HEV) infections are emerging in western countries[1]
We demonstrate that (1) HEV is highly sensitive to pegylated interferon-α (pegIFNα) treatment in vivo; (2) HEV infection in human hepatocytes doesn’t elicit an innate immune response; (3) HEV gt[1] presents higher viral loads compared to HEV gt[3]
PegIFNα associated viral clearance was accompanied by an increase of intrahepatic human interferon stimulated gene (ISG) and serum CXCL10 levels

Summary

Introduction

Hepatitis E Virus (HEV) infections are emerging in western countries[1]. HEV is a non-enveloped positive-sense single-stranded RNA virus, belonging to the family Hepeviridae within the genus Orthohepevirus[2]. On the other hand, increasing rates of chronic gt[3] infections have been described in immunocompromised patients in Europe, resulting in progressive liver fibrosis and cirrhosis[6,7,8] These data indicate that host pathogen interactions differ between both genotypes. We demonstrate that HEV gt[1] infections lead to higher virus loads in mouse feces, bile and liver compared to HEV gt[3] infections, without the induction of intrahepatic human innate immune responses Both HEV genotypes, but not Hepatitis B virus (HBV), are cleared after a few doses of pegIFNα in vivo, an effect accompanied by a clear increase of human ISG transcript levels in liver and of circulating human CXCL10 levels in mouse serum

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