Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

Michael Hermann Wißing; Toni Luise Meister; Maximilian Klaus Nocke; André Gömer; Mejrema Masovic; Leonard Knegendorf; Yannick Brüggemann; Verian Bader; Anindya Siddharta; Claus Thomas Bock; Alexander Ploss; Scott P. Kenney; Konstanze F. Winklhofer; Patrick Behrendt; Heiner Wedemeyer; Eike Steinmann; Daniel Todt

doi:10.1038/s41467-024-49219-8

Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

Michael Hermann Wißing, Toni Luise Meister, Maximilian Klaus Nocke, André Gömer, Mejrema Masovic, Leonard Knegendorf, Yannick Brüggemann, Verian Bader, Anindya Siddharta, Claus Thomas Bock, Alexander Ploss, Scott P. Kenney, Konstanze F. Winklhofer, Patrick Behrendt, Heiner Wedemeyer, Eike Steinmann, Daniel Todt

Princeton University

Research output: Contribution to journal › Article › peer-review

Abstract

Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.

Original language	American English
Article number	4855
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-49219-8
State	Published - Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Wißing, M. H., Meister, T. L., Nocke, M. K., Gömer, A., Masovic, M., Knegendorf, L., Brüggemann, Y., Bader, V., Siddharta, A., Bock, C. T., Ploss, A., Kenney, S. P., Winklhofer, K. F., Behrendt, P., Wedemeyer, H., Steinmann, E., & Todt, D. (2024). Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication. Nature communications, 15(1), Article 4855. https://doi.org/10.1038/s41467-024-49219-8

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title = "Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication",

abstract = "Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.",

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Wißing, MH, Meister, TL, Nocke, MK, Gömer, A, Masovic, M, Knegendorf, L, Brüggemann, Y, Bader, V, Siddharta, A, Bock, CT, Ploss, A, Kenney, SP, Winklhofer, KF, Behrendt, P, Wedemeyer, H, Steinmann, E & Todt, D 2024, 'Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication', Nature communications, vol. 15, no. 1, 4855. https://doi.org/10.1038/s41467-024-49219-8

TY - JOUR

T1 - Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

AU - Wißing, Michael Hermann

AU - Meister, Toni Luise

AU - Nocke, Maximilian Klaus

AU - Gömer, André

AU - Masovic, Mejrema

AU - Knegendorf, Leonard

AU - Brüggemann, Yannick

AU - Bader, Verian

AU - Siddharta, Anindya

AU - Bock, Claus Thomas

AU - Ploss, Alexander

AU - Kenney, Scott P.

AU - Winklhofer, Konstanze F.

AU - Behrendt, Patrick

AU - Wedemeyer, Heiner

AU - Steinmann, Eike

AU - Todt, Daniel

PY - 2024/12

Y1 - 2024/12

N2 - Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.

AB - Hepatitis E virus (HEV) is a long-neglected RNA virus and the major causative agent of acute viral hepatitis in humans. Recent data suggest that HEV has a very heterogeneous hypervariable region (HVR), which can tolerate major genomic rearrangements. In this study, we identify insertions of previously undescribed sequence snippets in serum samples of a ribavirin treatment failure patient. These insertions increase viral replication while not affecting sensitivity towards ribavirin in a subgenomic replicon assay. All insertions contain a predicted nuclear localization sequence and alanine scanning mutagenesis of lysine residues in the HVR influences viral replication. Sequential replacement of lysine residues additionally alters intracellular localization in a fluorescence dye-coupled construct. Furthermore, distinct sequence patterns outside the HVR are identified as viral determinants that recapitulate the enhancing effect. In conclusion, patient-derived insertions can increase HEV replication and synergistically acting viral determinants in and outside the HVR are described. These results will help to understand the underlying principles of viral adaptation by viral- and host-sequence snatching during the clinical course of infection.

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JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4855

ER -

Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication

Abstract

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