Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure

Autor: Smith, David A., Fernandez-Antunez, Carlota, Magri, Andrea, Bowden, Rory, Chaturvedi, Nimisha, Fellay, Jacques, McLauchlan, John, Foster, Graham R., Irving, William L., Simmonds, Peter, Pedergnana, Vincent, Ramirez, Santseharay, Bukh, Jens, Barnes, Eleanor, Ansari, M. Azim, Ball, Jonathan, Brainard, Diana, Burgess, Gary, Cooke, Graham, Dillon, John, Gore, Charles, Guha, Neil, Halford, Rachel, Herath, Cham, Holmes, Chris, Howe, Anita, Hudson, Emma, Irving, William, Khakoo, Salim, Klenerman, Paul, Koletzki, Diana, Martin, Natasha, Massetto, Benedetta, Mbisa, Tamyo, McHutchison, John, McKeating, Jane, Miners, Alec, Murray, Andrea, Shaw, Peter, Spencer, Chris C. A., Targett-Adams, Paul, Thomson, Emma, Vickerman, Peter, Zitzmann, Nicole
Přispěvatelé: Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford, University of Copenhagen = Københavns Universitet (UCPH), The Wellcome Trust Centre for Human Genetics [Oxford], Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne = University of Lausanne (UNIL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Glasgow, Queen Mary University of London (QMUL), University of Nottingham, UK (UON), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), STOP-HCV Consortium, Ball, J., Brainard, D., Burgess, G., Cooke, G., Dillon, J., Gore, C., Guha, N., Halford, R., Herath, C., Holmes, C., Howe, A., Hudson, E., Irving, W., Khakoo, S., Klenerman, P., Koletzki, D., Martin, N., Massetto, B., Mbisa, T., McHutchison, J., McKeating, J., Miners, A., Murray, A., Shaw, P., Spencer, CCA, Targett-Adams, P., Thomson, E., Vickerman, P., Zitzmann, N.
Jazyk: angličtina
Rok vydání: 2021
Předmět:
ns2
Sofosbuvir
[SDV]Life Sciences [q-bio]
viruses
General Physics and Astronomy
Genome-wide association study
resistance-associated substitutions
Hepacivirus
Viral Nonstructural Proteins
Chronic liver disease
medicine.disease_cause
chemistry.chemical_compound
0302 clinical medicine
Treatment Failure
0303 health sciences
Multidisciplinary
Hepatitis C virus
virus diseases
Viral Load
Antivirals
3. Good health
Hepatocellular carcinoma
030211 gastroenterology & hepatology
Viral load
medicine.drug
Genotype
ribavirin
Science
Genome
Viral
Antiviral Agents/therapeutic use
Genome
Viral/genetics
Hepacivirus/drug effects
Hepacivirus/genetics
Hepacivirus/isolation & purification
Hepatitis C
Chronic/drug therapy
Hepatitis C
Chronic/virology
Humans
Polymorphism
Genetic
Sofosbuvir/therapeutic use
Viral Load/drug effects
Viral Load/genetics
Viral Nonstructural Proteins/genetics
Antiviral Agents
General Biochemistry
Genetics and Molecular Biology
Article
Virus
03 medical and health sciences
medicine
Potency
emergence
030304 developmental biology
NS3
business.industry
Ribavirin
General Chemistry
biochemical phenomena
metabolism
and nutrition
Hepatitis C
Chronic
medicine.disease
Virology
infection
digestive system diseases
chemistry
Viral infection
protein
business
Zdroj: Nature Communications
Nature Communications, Vol 12, Iss 1, Pp 1-11 (2021)
STOP-HCV Consortium 2021, ' Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure ', Nature Communications, vol. 12, no. 1, 6105 . https://doi.org/10.1038/s41467-021-25649-6
Nature Communications, 2021, 12 (1), pp.6105. ⟨10.1038/s41467-021-25649-6⟩
Nature communications, vol. 12, no. 1, pp. 6105
ISSN: 2041-1723
DOI: 10.1038/s41467-021-25649-6
Popis: Sofosbuvir is a common therapy in hepatitis C virus infection, which targets the NS5B polymerase. Here, Smith et al. analyze the association between whole genome HCV polymorphisms and sofosbuvir treatment failure and identify three common polymorphisms present in non-targeted NS2 and NS3 proteins associated with reduced treatment response.
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.
Databáze: OpenAIRE
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