Both interferon alpha and lambda can reduce all intrahepatic HDV infection markers in HBV/HDV infected humanized mice

Katja Giersch,Katja Giersch,Maria Buti,Jörg Petersen,Tassilo Volz,Tassilo Volz,Camille Sureau,Lena Allweiss,Maria Homs,Marc Lütgehetmann,Marc Lütgehetmann,Ansgar W Lohse,Ansgar W Lohse,Ansgar W Lohse,Lena Allweiss,Jörg Petersen,Martina Helbig,Teresa Pollicino,Maura Dandri,Maura Dandri,Maura Dandri

doi:10.1038/s41598-017-03946-9

Abstract

Co-infection with hepatitis B (HBV) and D virus (HDV) is associated with the most severe course of liver disease. Interferon represents the only treatment currently approved. However, knowledge about the impact of interferons on HDV in human hepatocytes is scant. Aim was to assess the effect of pegylated interferon alpha (peg-IFNα) and lambda (peg-IFNλ), compared to the HBV-polymerase inhibitor entecavir (ETV) on all HDV infection markers using human liver chimeric mice and novel HDV strand-specific qRT-PCR and RNA in situ hybridization assays, which enable intrahepatic detection of HDV RNA species. Peg-IFNα and peg-IFNλ reduced HDV viremia (1.4 log and 1.2 log, respectively) and serum HBsAg levels (0.9-log and 0.4-log, respectively). Intrahepatic quantification of genomic and antigenomic HDV RNAs revealed a median ratio of 22:1 in untreated mice, resembling levels determined in HBV/HDV infected patients. Both IFNs greatly reduced intrahepatic levels of genomic and antigenomic HDV RNA, increasing the amounts of HDAg- and antigenomic RNA-negative hepatocytes. ETV-mediated suppression of HBV replication (2.1-log) did not significantly affect HBsAg levels, HDV productivity and/or release. In humanized mice lacking adaptive immunity, IFNs but not ETV suppressed HDV. Viremia decrease reflected the intrahepatic reduction of all HDV markers, including the antigenomic template, suggesting that intracellular HDV clearance is achievable.

Highlights

Around 15 million people worldwide are chronically infected with hepatitis Delta virus (HDV)
hepatitis B virus (HBV)/HDV co-infected human chimeric UPA/SCID/beige (USB) mice displaying comparable viremia levels received peg-IFNα (25ng/g body weight, n = 3), peg-IFNλ (25ng/g body weight, n = 3) or ETV (1 μg/ml supplemented in drinking water, n = 4) for four weeks or remained untreated as controls (n = 3 for each treatment group)
Administration of ETV led to a stronger decrease of HBV viremia (Fig. 1G), whereas HDV viremia (Fig. 1H) and HBsAg levels (Fig. 1I) did not change substantially after four weeks of treatment compared to median levels determined in matched control animals

Summary

Introduction

Around 15 million people worldwide are chronically infected with hepatitis Delta virus (HDV). Treatment options for chronically HBV/HDV co-infected patients are limited to interferons and pegylated interferon alpha (peg-IFNα) is the only currently approved treatment. The aim of this study was to investigate the impact of both pegylated interferon alpha and lambda, which were reported to have similar antiviral effects in chronic HBV infected patients[12], on HDV replication in vivo, by using human liver chimeric mice[13] and focussing on intrahepatic changes of the different HDV infection markers. We investigated the effects of the different treatments in HBV/HDV co-infected human hepatocytes by establishing a new magnetic beads-based qRT-PCR assay enabling specific quantification of both genomic and antigenomic HDV RNA forms in chimeric mice and patient liver samples, as well as a RNA in situ hybridization technique allowing the analysis of HDV RNA expression at single cell level

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Conclusion