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

Virus Replication / genetics Hepatitis E virus / genetics Humans Hepatitis E / virology Ribavirin / pharmacology Mutagenesis, Insertional Antiviral Agents / pharmacology RNA, Viral / genetics Genome, Viral Replicon / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
06 Jun 2024
Historique:
received: 06 10 2023
accepted: 24 05 2024
medline: 7 6 2024
pubmed: 7 6 2024
entrez: 6 6 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-49219-8 PMID: 38844458
pubmed: 38844458
doi: 10.1038/s41467-024-49219-8
pii: 10.1038/s41467-024-49219-8
doi:

Substances chimiques

Ribavirin 49717AWG6K
Antiviral Agents 0
RNA, Viral 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

4855

Subventions

Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 448974291
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : INST 213/840-1 FUGG
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : 510558817
Organisme : Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
ID : 01KI2106
Organisme : Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)
ID : 01EK2106A
Organisme : Bundesministerium für Gesundheit (Federal Ministry of Health, Germany)
ID : ZMVI1-2518FSB705
Organisme : Deutsches Zentrum für Infektionsforschung (German Center for Infection Research)
ID : TTU 05.823_00

Informations de copyright

© 2024. The Author(s).

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Auteurs

Michael Hermann Wißing (MH)

Department for Molecular and Medical Medicine, Ruhr University Bochum, Bochum, Germany.

Toni Luise Meister (TL)

Department for Molecular and Medical Medicine, Ruhr University Bochum, Bochum, Germany.
Institute for Infection Research and Vaccine Development (IIRVD), Centre for Internal Medicine, University Medical Centre Hamburg-Eppendorf (UKE), Hamburg, Germany.
Department for Clinical Immunology of Infectious Diseases, Bernhard Nocht Institute for Tropical Medicine (BNITM), Hamburg, Germany.
German Centre for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany.
ORCID: 0000-0001-8962-9443

Maximilian Klaus Nocke (MK)

Department for Molecular and Medical Medicine, Ruhr University Bochum, Bochum, Germany.
European Virus Bioinformatics Center (EVBC), Jena, Germany.

André Gömer (A)

Department for Molecular and Medical Medicine, Ruhr University Bochum, Bochum, Germany.

Mejrema Masovic (M)

Department for Molecular and Medical Medicine, Ruhr University Bochum, Bochum, Germany.

Leonard Knegendorf (L)

Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
Hannover Medical School, Institute for Medical Microbiology and Hospital Epidemiology, Hannover, Germany.
ORCID: 0000-0001-8469-1248

Yannick Brüggemann (Y)

Department for Molecular and Medical Medicine, Ruhr University Bochum, Bochum, Germany.

Verian Bader (V)

Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany.
Department of Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany.
ORCID: 0000-0001-5260-4728

Anindya Siddharta (A)

Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.

Claus-Thomas Bock (CT)

Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany.
ORCID: 0000-0002-2773-486X

Alexander Ploss (A)

Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
ORCID: 0000-0001-9322-7252

Scott P Kenney (SP)

Center for Food Animal Health, Departments of Animal Sciences and Veterinary Preventive Medicine, The Ohio State University, Wooster, OH, 43210, USA.

Konstanze F Winklhofer (KF)

Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany.
Cluster of Excellence RESOLV, Bochum, Germany.

Patrick Behrendt (P)

Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany.
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Braunschweig, Germany.

Heiner Wedemeyer (H)

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
German Center for Infectious Disease Research (DZIF); Partner Sites Hannover-Braunschweig, Braunschweig, Germany.
Excellence Cluster 2155 RESIST, Hannover Medical School, Hannover, Germany, Braunschweig, Germany.

Eike Steinmann (E)

Department for Molecular and Medical Medicine, Ruhr University Bochum, Bochum, Germany. Eike.Steinmann@ruhr-uni-bochum.de.
German Centre for Infection Research (DZIF), External Partner Site, Bochum, Germany. Eike.Steinmann@ruhr-uni-bochum.de.
ORCID: 0000-0002-3654-9965

Daniel Todt (D)

Department for Molecular and Medical Medicine, Ruhr University Bochum, Bochum, Germany. Daniel.Todt@ruhr-uni-bochum.de.
European Virus Bioinformatics Center (EVBC), Jena, Germany. Daniel.Todt@ruhr-uni-bochum.de.
ORCID: 0000-0002-3564-1014

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Classifications MeSH

questionsmedicales.fr › Phénomènes microbiologiques › Phénomènes physiologiques viraux › Réplication virale › Genetic determinants of host- and...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Hepevirus › Virus de l'hépatite E › Genetic determinants of host- and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genetic determinants of host- and...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Hépatite › Hépatites virales humaines › Hépatite E › Genetic determinants of host- and...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Ribonucléosides › Ribavirine › Genetic determinants of host- and...
questionsmedicales.fr › Phénomènes génétiques › Mutagenèse › Mutagenèse par insertion › Genetic determinants of host- and...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiviraux › Genetic determinants of host- and...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN viral › Genetic determinants of host- and...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Génome microbien › Génome viral › Genetic determinants of host- and...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Réplicon › Genetic determinants of host- and...