Highly replicating hepatitis C virus variants emerge in immunosuppressed patients causing severe disease
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.
Authors
- A. Sarah Walker (ORCID: https://orcid.org/0000-0002-0412-8509)
- Stephen Ryder (ORCID: https://orcid.org/0000-0001-9649-4444)
- Emily Dennis (ORCID: https://orcid.org/0000-0002-9634-7767)
- Andrew R. Lloyd (ORCID: https://orcid.org/0000-0001-6277-8887)
- Stephen T. Barclay (ORCID: https://orcid.org/0000-0003-0415-785X)
- Jane Collier
- Sanjay R. Bhagani (ORCID: https://orcid.org/0000-0003-2557-4337)
- Martin Wiselka (ORCID: https://orcid.org/0000-0002-4587-5826)
- Marvin Reineke (ORCID: https://orcid.org/0000-0001-6749-3426)
- Daniel Forton (ORCID: https://orcid.org/0000-0002-0903-9169)
- Sarah Pett (ORCID: https://orcid.org/0000-0002-4851-4727)
- Jonathan R. Honegger (ORCID: https://orcid.org/0000-0002-3181-0554)
- Dung Nguyen (ORCID: https://orcid.org/0000-0001-9390-9990)
- Eleanor Barnes (ORCID: https://orcid.org/0000-0002-0860-0831)
- Chaturaka Rodrigo (ORCID: https://orcid.org/0000-0003-2189-9177)
- Aftab Ala (ORCID: https://orcid.org/0000-0001-6257-3160)
- Sumita Verma (ORCID: https://orcid.org/0000-0001-7021-8409)
- Maike Hofmann (ORCID: https://orcid.org/0000-0001-8410-8833)
- Alina C. Schneider
- Margaret Tulessin (ORCID: https://orcid.org/0009-0009-3854-5288)
- Jörg Timm (ORCID: https://orcid.org/0000-0001-7799-3045)
- Robert Thimme (ORCID: https://orcid.org/0000-0003-1417-4135)
- Uta Merle (ORCID: https://orcid.org/0000-0003-1386-3350)
- Volker Lohmann (ORCID: https://orcid.org/0000-0001-8719-7608)
- Leanne McCabe (ORCID: https://orcid.org/0000-0002-6509-8999)
- Christopher R. Jones (ORCID: https://orcid.org/0000-0002-6301-2282)
- Louise Benning (ORCID: https://orcid.org/0000-0002-8366-2100)
- Rowena Anne Bull (ORCID: https://orcid.org/0000-0002-9844-3744)
- Ben Stone
- Graham Cooke (ORCID: https://orcid.org/0000-0001-6475-5056)
- Fleur Hudson (ORCID: https://orcid.org/0000-0001-5891-7514)
- Rachel Halford (ORCID: https://orcid.org/0000-0003-4569-2824)
- Stuart McPherson (ORCID: https://orcid.org/0000-0002-5638-2453)
- Carolin Mogler (ORCID: https://orcid.org/0000-0003-3400-7254)
- Chin Lye Ch’ng (ORCID: https://orcid.org/0000-0003-3179-9313)
- Richard Gilson (ORCID: https://orcid.org/0000-0002-9572-193X)
- M. Azim Ansari (ORCID: https://orcid.org/0000-0003-2790-8353)
- Wang Zhi-qing (ORCID: https://orcid.org/0009-0000-7672-1283)
- David A. Smith (ORCID: https://orcid.org/0000-0001-7778-7137)
- Mark Nelson (ORCID: https://orcid.org/0000-0002-5944-6096)
- Tomke Arand
Institutions
- Brighton and Sussex Medical School (GB)
- Swansea Bay University Health Board (GB)
- Nationwide Children's Hospital (US)
- Nottingham University Hospitals NHS Trust (GB)
- University of Freiburg (DE)
- Royal Free London NHS Foundation Trust (GB)
- Heidelberg University (DE)
- Chelsea and Westminster Hospital NHS Foundation Trust (GB)
- Glasgow Royal Infirmary (GB)
- University Medical Center Freiburg (DE)
- Unit of Virus Host Cell Interactions (FR)
- University Hospital Heidelberg (DE)
- University Hospitals of Leicester NHS Trust (GB)
- John Radcliffe Hospital (GB)
- University of Surrey (GB)
- UNSW Sydney (AU)
- University of Oxford (GB)
- The Hepatitis C Trust (GB)
- Medawar Building for Pathogen Research (GB)
- Sheffield Teaching Hospitals NHS Foundation Trust (GB)
- St George's Hospital (GB)
- Hospital Clínic de Barcelona (ES)
- German Center for Infection Research (DE)
- Newcastle upon Tyne Hospital (GB)
- Centre Hospitalier de l’Université de Montréal (CA)
- Science Oxford (GB)
- MRC University of Glasgow Centre for Virus Research (GB)
- Heinrich Heine University Düsseldorf (DE)
- University College London (GB)
- Imperial College London (GB)
- The Ohio State University (US)
- Technical University of Munich (DE)
- Université de Montréal (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-07
- DOI
- https://doi.org/10.1038/s41467-025-67174-w
- Citations
- 1
- Primary Topic
- Hepatitis C virus research
- Type
- article
- Field-Weighted Citation Impact
- 1.32
Funders
- Deutsches Zentrum für Infektionsforschung
- Centres de Recerca de Catalunya
- European Commission
- Deutsche Forschungsgemeinschaft
- Generalitat de Catalunya
- National Institutes of Health
- Canadian Institutes of Health Research
- Instituto de Salud Carlos III
- National Institute of Allergy and Infectious Diseases