Extrahepatic Replication and Genomic Signatures of the Hepatitis E Virus in the Kidney.

in Liver international : official journal of the International Association for the Study of the Liver by Avista Wahid, Nele Meyer, Christine Wundes, Lucas Hüffner, Saskia Janshoff, Nicola Frericks, Martina Friesland, Katja Dinkelborg, Elmira Aliabadi, Fenja Laue, Markus Cornberg, Benjamin Maasoumy, Birgit Bremer, Sven Pischke, Tobias Müller, Julian Zur Schulze Wiesch, Julia Benckert, Rainer G Ulrich, Svenja Hardtke, Petra Dörge, Florian Vondran, Ansgar Lohse, Michael Peter Manns, Daniel Todt, Heiner Wedemeyer, Thomas Pietschmann, Eike Steinmann, André Gömer, Patrick Behrendt

TLDR

  • Researchers studied how well Hepatitis E Virus (HEV) grows in kidney cells and how it related to antiviral treatment. They found that HEV grows well in kidney cells and that some antivirals may not work as well as expected.
  • Key Insights: HEV grows well in kidney cells, broad-spectrum antiviral ribavirin may not be effective in all cases, and compartmentalisation of HEV in different tissues may lead to distinct clinical outcomes.

Abstract

The hepatitis E virus (HEV; species Paslahepevirus balayani) is a common human pathogenic and zoonotic virus that can cause both acute fulminant and chronic hepatitis. Despite its reputation as a hepatotropic virus, HEV infection is also associated with a number of extrahepatic diseases, including kidney disorders. However, the extent to which HEV replicates in kidney cells remains unclear. The present study aims to investigate the capacity of HEV to propagate in kidney cells in vitro and to assess whether HEV displays mutational signatures that correlate with compartmentalisation in vivo. We use HEV cell culture models to study the replication cycle and the effect of antivirals in human kidney cell lines and primary cells. In addition, we identified patients with chronic HEV infection (n = 9) from which we then sequenced the viral RNA of urine, stools and plasma to analyse the viral sequence composition, to assess intra-host diversity and compartmentalisation (n = 2). A wide range of human kidney cell lines as well as primary cells supports viral entry, replication and propagation of HEV in vitro. Interestingly, the broad-spectrum antiviral ribavirin was less effective in inhibiting HEV replication in some kidney cells. Sequencing of HEV RNA-directed RNA polymerase coding region from plasma, stool and urine and subsequent phylogenetic analysis revealed diversification of HEV into tissue-specific viral subpopulations. In particular, the viruses derived from urine were found to be distinct from those derived from plasma and stool. In conclusion, kidney cells support the propagation of HEV in vitro and exhibit reduced sensitivity to antiviral treatment. Furthermore, HEV patient-derived sequences demonstrated compartmentalisation into distinct clusters that correlated with sample source. Collectively, these data indicate the potential for extrahepatic replication of HEV, which may result in clinically significant disease or serve as a reservoir for patient relapse. HepNet-SofE study (NCT03282474).

Overview

  • The study investigates the capacity of Hepatitis E Virus (HEV) to replicate in kidney cells in vitro and assesses whether HEV displays mutational signatures that correlate with compartmentalisation in vivo.
  • The study uses HEV cell culture models to study the replication cycle and the effect of antivirals in human kidney cell lines and primary cells.
  • The researchers identify patients with chronic HEV infection and sequence the viral RNA from urine, stools, and plasma to analyze the viral sequence composition and assess intra-host diversity and compartmentalisation.

Comparative Analysis & Findings

  • A wide range of human kidney cell lines and primary cells support viral entry, replication, and propagation of HEV in vitro.
  • The broad-spectrum antiviral ribavirin was less effective in inhibiting HEV replication in some kidney cells.
  • Sequencing of HEV RNA-directed RNA polymerase coding region from plasma, stool, and urine and subsequent phylogenetic analysis revealed diversification of HEV into tissue-specific viral subpopulations.

Implications and Future Directions

  • The study suggests that kidney cells may support the propagation of HEV in vitro, which may result in clinically significant disease or serve as a reservoir for patient relapse.
  • The finding that HEV patient-derived sequences demonstrated compartmentalisation into distinct clusters that correlated with sample source highlights the need for further research into the mechanisms of HEV compartmentalisation.
  • Future studies could investigate the clinical significance of extrahepatic HEV replication and explore potential therapeutic strategies for treating HEV infections in the kidney.
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