Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 10 2021
20 10 2021
Historique:
received:
04
06
2020
accepted:
11
08
2021
entrez:
21
10
2021
pubmed:
22
10
2021
medline:
20
11
2021
Statut:
epublish
Résumé
Persistent hepatitis C virus (HCV) infection is a major cause of chronic liver disease, worldwide. With the development of direct-acting antivirals, treatment of chronically infected patients has become highly effective, although a subset of patients responds less well to therapy. Sofosbuvir is a common component of current de novo or salvage combination therapies, that targets the HCV NS5B polymerase. We use pre-treatment whole-genome sequences of HCV from 507 patients infected with HCV subtype 3a and treated with sofosbuvir containing regimens to detect viral polymorphisms associated with response to treatment. We find three common polymorphisms in non-targeted HCV NS2 and NS3 proteins are associated with reduced treatment response. These polymorphisms are enriched in post-treatment HCV sequences of patients unresponsive to treatment. They are also associated with lower reductions in viral load in the first week of therapy. Using in vitro short-term dose-response assays, these polymorphisms do not cause any reduction in sofosbuvir potency, suggesting an indirect mechanism of action in decreasing sofosbuvir efficacy. The identification of polymorphisms in NS2 and NS3 proteins associated with poor treatment outcomes emphasises the value of systematic genome-wide analyses of viruses in uncovering clinically relevant polymorphisms that impact treatment.
Identifiants
pubmed: 34671027
doi: 10.1038/s41467-021-25649-6
pii: 10.1038/s41467-021-25649-6
pmc: PMC8528821
doi:
Substances chimiques
Antiviral Agents
0
NS2 protein, Hepatitis C virus
0
NS3 protein, hepatitis C virus
0
Viral Nonstructural Proteins
0
Sofosbuvir
WJ6CA3ZU8B
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6105Subventions
Organisme : Wellcome Trust
ID : 206296/Z/17/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 203141/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12014/1
Pays : United Kingdom
Organisme : Wellcome Trust (Wellcome)
ID : 220171/Z/20/Z
Organisme : Medical Research Council
ID : MR/K01532X/1
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Investigateurs
Jonathan Ball
(J)
Diana Brainard
(D)
Gary Burgess
(G)
Graham Cooke
(G)
John Dillon
(J)
Charles Gore
(C)
Neil Guha
(N)
Rachel Halford
(R)
Cham Herath
(C)
Chris Holmes
(C)
Anita Howe
(A)
Emma Hudson
(E)
William Irving
(W)
Salim Khakoo
(S)
Paul Klenerman
(P)
Diana Koletzki
(D)
Natasha Martin
(N)
Benedetta Massetto
(B)
Tamyo Mbisa
(T)
John McHutchison
(J)
Jane McKeating
(J)
Alec Miners
(A)
Andrea Murray
(A)
Peter Shaw
(P)
Chris C A Spencer
(CCA)
Paul Targett-Adams
(P)
Emma Thomson
(E)
Peter Vickerman
(P)
Nicole Zitzmann
(N)
Informations de copyright
© 2021. The Author(s).
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