Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication
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Genetic determinants of host- and virus-derived insertions for hepatitis E virus replication. / Wißing, Michael Hermann; Meister, Toni Luise; Nocke, Maximilian Klaus; Gömer, André; Masovic, Mejrema; Knegendorf, Leonard; Brüggemann, Yannick; Bader, Verian; Siddharta, Anindya; Bock, Claus-Thomas; Ploss, Alexander; Kenney, Scott P; Winklhofer, Konstanze F; Behrendt, Patrick; Wedemeyer, Heiner; Steinmann, Eike; Todt, Daniel.
in: NAT COMMUN, Jahrgang 15, Nr. 1, 06.06.2024, S. 4855.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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
N1 - © 2024. The Author(s).
PY - 2024/6/6
Y1 - 2024/6/6
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.
KW - Virus Replication/genetics
KW - Hepatitis E virus/genetics
KW - Humans
KW - Hepatitis E/virology
KW - Ribavirin/pharmacology
KW - Mutagenesis, Insertional
KW - Antiviral Agents/pharmacology
KW - RNA, Viral/genetics
KW - Genome, Viral
KW - Replicon/genetics
U2 - 10.1038/s41467-024-49219-8
DO - 10.1038/s41467-024-49219-8
M3 - SCORING: Journal article
C2 - 38844458
VL - 15
SP - 4855
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -