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; Marvin Reineke; Louise Benning; Jonathan Honegger; Maike Hofmann; Robert Thimme; Jörg Timm; Graham S. Cooke; Sarah Pett; Leanne McCabe; Chris Jones; Richard Gilson; Sumita Verma; Stephen D. Ryder; Jane D. Collier; Stephen T. Barclay; Aftab Ala; Sanjay Bhagani; Mark Nelson; Chin Lye Ch’ng; Ben Stone; Martin Wiselka; Daniel Forton; Stuart McPherson; Rachel Halford; Dung Nguyen; David Smith; Emily Dennis; Fleur Hudson; Eleanor J. Barnes; Ann Sarah Walker; 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

doi:10.1038/s41467-025-67174-w

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

P Paul Rothhaar T Tomke Arand H Ha Gyu-Thomas Seong C Christian Heuss M Margaret Tulessin Z Zhiqing Wang C Colin Förster A Alina C. Schneider J Jocelyn Quistrebert H Haiting Chai M Marvin Reineke L Louise Benning J Jonathan Honegger M Maike Hofmann R Robert Thimme J Jörg Timm G Graham S. Cooke S Sarah Pett L Leanne McCabe C Chris Jones R Richard Gilson S Sumita Verma S Stephen D. Ryder J Jane D. Collier S Stephen T. Barclay A Aftab Ala S Sanjay Bhagani M Mark Nelson C Chin Lye Ch’ng B Ben Stone M Martin Wiselka D Daniel Forton S Stuart McPherson R Rachel Halford D Dung Nguyen D David Smith E Emily Dennis F Fleur Hudson E Eleanor J. Barnes A Ann Sarah Walker P Paul Schnitzler U Uta Merle N Naglaa H. Shoukry J Julie Bruneau C Chaturaka Rodrigo A Andrew Lloyd R Rowena A. Bull (University of New South Wales Sydney, School of Biomedical Sciences, Faculty of Medicine) M M. Azim Ansari C Carolin Mogler J John McLauchlan X Xavier Forns S Sofía Pérez-del-Pulgar V Volker Lohmann

Abstract

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.

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Article Details

Journal Nature Communications

Volume / Issue Vol. 16, Issue 1

Published December 07, 2025

DOI 10.1038/s41467-025-67174-w

ISSN 2041-1723

Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (53)

P

Paul Rothhaar

T

Tomke Arand

H

Ha Gyu-Thomas Seong

C

Christian Heuss

M

Margaret Tulessin

Z

Zhiqing Wang

C

Colin Förster

A

Alina C. Schneider

J

Jocelyn Quistrebert

H

Haiting Chai

M

Marvin Reineke

L

Louise Benning

J

Jonathan Honegger

M

Maike Hofmann

R

Robert Thimme

J

Jörg Timm

G

Graham S. Cooke

S

Sarah Pett

L

Leanne McCabe

C

Chris Jones

R

Richard Gilson

S

Sumita Verma

S

Stephen D. Ryder

J

Jane D. Collier

S

Stephen T. Barclay

A

Aftab Ala

S

Sanjay Bhagani

M

Mark Nelson

C

Chin Lye Ch’ng

B

Ben Stone

M

Martin Wiselka

D

Daniel Forton

S

Stuart McPherson

R

Rachel Halford

D

Dung Nguyen

D

David Smith

E

Emily Dennis

F

Fleur Hudson

E

Eleanor J. Barnes

A

Ann Sarah Walker

P

Paul Schnitzler

U

Uta Merle

N

Naglaa H. Shoukry

J

Julie Bruneau

C

Chaturaka Rodrigo

A

Andrew Lloyd

R

Rowena A. Bull

University of New South Wales Sydney, School of Biomedical Sciences, Faculty of Medicine

M

M. Azim Ansari

C

Carolin Mogler

J

John McLauchlan

X

Xavier Forns

S

Sofía Pérez-del-Pulgar

V

Volker Lohmann

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

Abstract

Article Details

Journal Info

Authors (53)

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