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Genetic Diversity and Evolution

Broad and Dynamic Diversification of Infectious Hepatitis C Virus in a Cell Culture Environment

Isabel Gallego, María Eugenia Soria, Carlos García-Crespo, Qian Chen, Patricia Martínez-Barragán, Soumaya Khalfaoui, Brenda Martínez-González, Irene Sanchez-Martin, Inés Palacios-Blanco, Ana Isabel de Ávila, Damir García-Cehic, Juan Ignacio Esteban, Jordi Gómez, Carlos Briones, Josep Gregori, Josep Quer, Celia Perales, Esteban Domingo
J.-H. James Ou, Editor
Isabel Gallego
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
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María Eugenia Soria
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
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Carlos García-Crespo
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
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Qian Chen
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
cLiver Unit, Internal Medicine Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain
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Patricia Martínez-Barragán
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
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Soumaya Khalfaoui
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
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Brenda Martínez-González
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
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Irene Sanchez-Martin
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
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Inés Palacios-Blanco
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
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Ana Isabel de Ávila
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
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Damir García-Cehic
bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
cLiver Unit, Internal Medicine Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain
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Juan Ignacio Esteban
bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
cLiver Unit, Internal Medicine Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain
eUniversitat Autónoma de Barcelona, Barcelona, Spain
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Jordi Gómez
bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
fInstituto de Parasitología y Biomedicina “López-Neyra” (IPBLN, CSIC), Parque Tecnológico Ciencias de la Salud, Armilla, Granada, Spain
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Carlos Briones
bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
gCentro de Astrobiología (CAB, CSIC-INTA), Madrid, Spain
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Josep Gregori
bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
cLiver Unit, Internal Medicine Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain
dRoche Diagnostics, S.L., Sant Cugat del Vallés, Barcelona, Spain
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Josep Quer
bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
cLiver Unit, Internal Medicine Hospital Universitari Vall d’Hebron, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain
eUniversitat Autónoma de Barcelona, Barcelona, Spain
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Celia Perales
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
hDepartment of Clinical Microbiology, IIS-Fundación Jiménez Díaz, Madrid, Spain
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Esteban Domingo
aCentro de Biología Molecular “Severo Ochoa” (CBMSO, CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
bCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, Madrid, Spain
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J.-H. James Ou
University of Southern California
Roles: Editor
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DOI: 10.1128/JVI.01856-19
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ABSTRACT

Previous studies documented that long-term hepatitis C virus (HCV) replication in human hepatoma Huh-7.5 cells resulted in viral fitness gain, expansion of the mutant spectrum, and several phenotypic alterations. In the present work, we show that mutational waves (changes in frequency of individual mutations) occurred continuously and became more prominent as the virus gained fitness. They were accompanied by an increasing proportion of heterogeneous genomic sites that affected 1 position in the initial HCV population and 19 and 69 positions at passages 100 and 200, respectively. Analysis of biological clones of HCV showed that these dynamic events affected infectious genomes, since part of the fluctuating mutations became incorporated into viable genomes. While 17 mutations were scored in 3 biological clones isolated from the initial population, the number reached 72 in 3 biological clones from the population at passage 200. Biological clones differed in their responses to antiviral inhibitors, indicating a phenotypic impact of viral dynamics. Thus, HCV adaptation to a specific constant environment (cell culture without external influences) broadens the mutant repertoire and does not focus the population toward a limited number of dominant genomes. A retrospective examination of mutant spectra of foot-and-mouth disease virus passaged in cell cultures suggests a parallel behavior here described for HCV. We propose that virus diversification in a constant environment has its basis in the availability of multiple alternative mutational pathways for fitness gain. This mechanism of broad diversification should also apply to other replicative systems characterized by high mutation rates and large population sizes.

IMPORTANCE The study shows that extensive replication of an RNA virus in a constant biological environment does not limit exploration of sequence space and adaptive options. There was no convergence toward a restricted set of adapted genomes. Mutational waves and mutant spectrum broadening affected infectious genomes. Therefore, profound modifications of mutant spectrum composition and consensus sequence diversification are not exclusively dependent on environmental alterations or the intervention of population bottlenecks.

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Broad and Dynamic Diversification of Infectious Hepatitis C Virus in a Cell Culture Environment
Isabel Gallego, María Eugenia Soria, Carlos García-Crespo, Qian Chen, Patricia Martínez-Barragán, Soumaya Khalfaoui, Brenda Martínez-González, Irene Sanchez-Martin, Inés Palacios-Blanco, Ana Isabel de Ávila, Damir García-Cehic, Juan Ignacio Esteban, Jordi Gómez, Carlos Briones, Josep Gregori, Josep Quer, Celia Perales, Esteban Domingo
Journal of Virology Feb 2020, 94 (6) e01856-19; DOI: 10.1128/JVI.01856-19

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Broad and Dynamic Diversification of Infectious Hepatitis C Virus in a Cell Culture Environment
Isabel Gallego, María Eugenia Soria, Carlos García-Crespo, Qian Chen, Patricia Martínez-Barragán, Soumaya Khalfaoui, Brenda Martínez-González, Irene Sanchez-Martin, Inés Palacios-Blanco, Ana Isabel de Ávila, Damir García-Cehic, Juan Ignacio Esteban, Jordi Gómez, Carlos Briones, Josep Gregori, Josep Quer, Celia Perales, Esteban Domingo
Journal of Virology Feb 2020, 94 (6) e01856-19; DOI: 10.1128/JVI.01856-19
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KEYWORDS

RNA virus evolution
viral quasispecies
sequence space
adaptation
mutant spectrum
mutational waves

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