Evidence map›Paper›PMID 41354652›Full record

ArticleNature communications2025

Highly replicating hepatitis C virus variants emerge in immunosuppressed patients causing severe disease.

Paul Rothhaar, Tomke Arand, Ha Gyu-Thomas Seong, Christian Heuss, Margaret Tulessin, Zhiqing Wang, Colin Förster, Alina C Schneider, Jocelyn Quistrebert, Haiting Chai and 20 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

30 authors.

Paul RothhaarDepartment of Infectious Diseases, Molecular Virology, Section Virus-Host interactions, Heidelberg University, Heidelberg, Germany.ORCID http://orcid.org/0000-0002-9281-0371
Tomke ArandDepartment of Infectious Diseases, Molecular Virology, Section Virus-Host interactions, Heidelberg University, Heidelberg, Germany.
Ha Gyu-Thomas SeongDepartment of Infectious Diseases, Molecular Virology, Section Virus-Host interactions, Heidelberg University, Heidelberg, Germany.
Christian HeussDepartment of Infectious Diseases, Molecular Virology, Section Virus-Host interactions, Heidelberg University, Heidelberg, Germany.
Margaret TulessinInstitute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany.ORCID http://orcid.org/0009-0009-3854-5288
Zhiqing WangNuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.
Colin FörsterDepartment of Infectious Diseases, Molecular Virology, Section Virus-Host interactions, Heidelberg University, Heidelberg, Germany.ORCID http://orcid.org/0000-0002-4891-7104
Alina C SchneiderDepartment of Infectious Diseases, Molecular Virology, Section Virus-Host interactions, Heidelberg University, Heidelberg, Germany.
Jocelyn QuistrebertNuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.ORCID http://orcid.org/0000-0002-4973-3235
Haiting ChaiNuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.
Marvin ReinekeDepartment of Nephrology, University Hospital Heidelberg, Heidelberg, Germany.ORCID http://orcid.org/0000-0001-6749-3426
Louise BenningDepartment of Nephrology, University Hospital Heidelberg, Heidelberg, Germany.ORCID http://orcid.org/0000-0002-8366-2100
Jonathan HoneggerDepartment of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.ORCID http://orcid.org/0000-0002-3181-0554
Maike HofmannDepartment of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0001-8410-8833
Robert ThimmeDepartment of Medicine II, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0003-1417-4135
Jörg TimmInstitute of Virology, Faculty of Medicine, University of Duesseldorf, Duesseldorf, Germany.ORCID http://orcid.org/0000-0001-7799-3045
STOPHCV investigators
Paul SchnitzlerDepartment of Infectious Diseases Virology, University Hospital Heidelberg, Heidelberg, Germany.
Uta MerleDepartment of Internal Medicine IV, University Hospital Heidelberg, Heidelberg, Germany.ORCID http://orcid.org/0000-0003-1386-3350
Naglaa H ShoukryCentre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.ORCID http://orcid.org/0000-0002-8817-8238
Julie BruneauCentre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
Chaturaka RodrigoFaculty of Medicine, The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.ORCID http://orcid.org/0000-0003-2189-9177
Andrew LloydFaculty of Medicine, The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.ORCID http://orcid.org/0000-0001-6277-8887
Rowena A BullFaculty of Medicine, The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.ORCID http://orcid.org/0000-0002-9844-3744
M Azim AnsariNuffield Department of Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, UK.
Carolin MoglerInstitute of Pathology, School of Medicine and Health, Technical University of Munich, Munich, Germany.ORCID http://orcid.org/0000-0003-3400-7254
John McLauchlanMRC-University of Glasgow Centre for Virus Research, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Xavier FornsLiver Unit, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, CIBEREHD, Barcelona, Spain.
Sofía Pérez-Del-PulgarLiver Unit, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, CIBEREHD, Barcelona, Spain.
Volker LohmannDepartment of Infectious Diseases, Molecular Virology, Section Virus-Host interactions, Heidelberg University, Heidelberg, Germany. Volker.lohmann@med.uni-heidelberg.de.ORCID http://orcid.org/0000-0001-8719-7608

Funding

Protective immunity to HCV and rational vaccine designU19AI159819 · NIAID · EMORY UNIVERSITY · PI Arash Grakoui · 2021 to 2026
$16.6M
Persistent hepatitis C virus replication and T cell immunity in pregnancyR01AI096882 · NIAID · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · PI WALKER, CHRISTOPHER M. · 2012 to 2022
$5.7M
Deutsche Forschungsgemeinschaft (German Research Foundation) 272983813 - TRR 179Deutsche Forschungsgemeinschaft (German Research Foundation) 519777725Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) R01AI096882Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) U19AI159819Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada) PJT-173467NIAID NIH HHS R01 AI096882NIAID NIH HHS U19 AI159819
6 · The paper itself

Abstract

Hepatitis C virus (HCV) exists as a heterogenous quasispecies, but the phenotypic consequences of viral variability are widely unexplored. Here we identify a replication enhancing domain (ReED) in non-structural protein 5A conferring high replication fitness to clinical isolates. Accumulation of mutations in the ReED mediates high genome replication capacity. In a cohort of liver transplant patients, high replicator variants are exclusively found in individuals with severe disease outcome, suggesting that high viral replication fitness is associated with increased viral pathogenesis. Analysis of large sequence cohorts reveals that overall only 10% of viral genomes show genetic signatures of high replicators, which are enriched in recipients of liver transplantations, patients developing hepatocellular carcinoma and in HIV coinfected individuals. Overall, our data suggests that low replication fitness is a hallmark of HCV, contributing to establishment of persistence, whereas high replicators appear to have an advantage under conditions of immune suppression, thereby enforcing pathogenesis.

Indexed as

HepacivirusHepatitis CImmunocompromised HostVirus ReplicationCarcinoma, HepatocellularCoinfectionFemaleGenetic VariationGenome, ViralHIV InfectionsHumansLiver NeoplasmsLiver TransplantationMaleMutationRNA-Dependent RNA PolymeraseNS-5 protein, hepatitis C virusRNA-Dependent RNA PolymeraseViral Nonstructural Proteins

Identifiers

PMID41354652
PMCPMC12686413

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.