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

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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 mut...

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Main Authors: Rothhaar, Paul (Author) , Arand, Tomke (Author) , Seong, Thomas (Author) , Heuss, Christian (Author) , Tulessin, Margaret (Author) , Wang, Zhiqing (Author) , Förster, Colin (Author) , Schneider, Alina C. (Author) , Quistrebert, Jocelyn (Author) , Chai, Haiting (Author) , Reineke, Marvin (Author) , Benning, Louise (Author) , Honegger, Jonathan (Author) , Hofmann, Maike (Author) , Thimme, Robert (Author) , Timm, Jörg (Author) , Schnitzler, Paul (Author) , Merle, Uta (Author) , Shoukry, Naglaa H. (Author) , Bruneau, Julie (Author) , Rodrigo, Chaturaka (Author) , Lloyd, Andrew (Author) , Bull, Rowena A. (Author) , Ansari, M. Azim (Author) , Mogler, Carolin (Author) , McLauchlan, John (Author) , Forns, Xavier (Author) , Pérez-del-Pulgar, Sofía (Author) , Lohmann, Volker (Author)
Format: Article (Journal)
Language:English
Published: 07 December 2025
In: Nature Communications
Year: 2025, Pages: 1-37
ISSN:2041-1723
DOI:10.1038/s41467-025-67174-w
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-67174-w
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-67174-w
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Author Notes:Paul Rothhaar, Tomke Arand, Ha Gyu-Thomas Seong, Christian Heuss, Margaret Tulessin, Zhiqing Wang, Colin Förster, Alina C. Schneider, Jocelyn Quistrebert, Haiting Chai, Marvin Reineke, Louise Benning, Jonathan Honegger, Maike Hofmann, Robert Thimme, Jörg Timm, STOPHCV investigators, Paul Schnitzler, Uta Merle, Naglaa H. Shoukry, Julie Bruneau, Chaturaka Rodrigo, Andrew Lloyd, Rowena A. Bull, M. Azim Ansari, Carolin Mogler, John McLauchlan, Xavier Forns, Sofía Pérez-del-Pulgar & Volker Lohmann

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520 |a 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. 
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