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00925njm 22002777a 4500 dc García-Crespo, Carlos author Gallego, Isabel author Soria Benito, Maria Eugenia author de Ávila, Ana Isabel author Martínez-González, Brenda author Vázquez-Sirvent, Lucía author Quer Sivila, Josep author Gregori Font, Josep author 2021-12-28T10:55:17Z 2021-12-28T10:55:17Z 2021-04-03 Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Virus de l'hepatitis C; Vacunes universals Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Virus de la hepatitis C; Vacunas universales Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Hepatitis C virus; Universal vaccines Replication of RNA viruses is characterized by exploration of sequence space which facilitates their adaptation to changing environments. It is generally accepted that such exploration takes place mainly in response to positive selection, and that further diversification is boosted by modifications of virus population size, particularly bottleneck events. Our recent results with hepatitis C virus (HCV) have shown that the expansion in sequence space of a viral clone continues despite prolonged replication in a stable cell culture environment. Diagnosis of the expansion was based on the quantification of diversity indices, the occurrence of intra-population mutational waves (variations in mutant frequencies), and greater individual residue variations in mutant spectra than those anticipated from sequence alignments in data banks. In the present report, we review our previous results, and show additionally that mutational waves in amplicons from the NS5A-NS5B-coding region are equally prominent during HCV passage in the absence or presence of the mutagenic nucleotide analogues favipiravir or ribavirin. In addition, by extending our previous analysis to amplicons of the NS3- and NS5A-coding region, we provide further evidence of the incongruence between amino acid conservation scores in mutant spectra from infected patients and in the Los Alamos National Laboratory HCV data banks. We hypothesize that these observations have as a common origin a permanent state of HCV population disequilibrium even upon extensive viral replication in the absence of external selective constraints or changes in population size. Such a persistent disequilibrium—revealed by the changing composition of the mutant spectrum—may facilitate finding alternative mutational pathways for HCV antiviral resistance. The possible significance of our model for other genetically variable viruses is discussed. The work at CBMSO was supported by grants SAF2014-52400-R from Ministerio de Economía y Competitividad (MINECO), SAF2017-87846-R and BFU2017-91384-EXP from Ministerio de Ciencia, Innovación y Universidades (MCIU), PI18/00210 from Instituto de Salud Carlos III, S2013/ABI-2906 (PLATESA from Comunidad de Madrid/FEDER), and S2018/BAA-4370 (PLATESA2 from Comunidad de Madrid/FEDER). C.P. is supported by the Miguel Servet program of the Instituto de Salud Carlos III (CPII19/00001), cofinanced by the European Regional Development Fund (ERDF). CIBERehd (Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas) is funded by Instituto de Salud Carlos III. Institutional grants from the Fundación Ramón Areces and Banco Santander to the CBMSO are also acknowledged. The team at CBMSO belongs to the Global Virus Network (GVN). The work in Barcelona was supported by Instituto de Salud Carlos III, cofinanced by the European Regional Development Fund (ERDF) Grant No. PI19/00301 and by the Centro para el Desarrollo Tecnológico Industrial (CDTI) from the MICIU, Grant No. IDI-20200297. Work at CAB was supported by MINECO grant BIO2016-79618R and PID2019-104903RB-I00 (funded by the EU under the FEDER program) and by the Spanish State research agency (AEI) through project number MDM-2017-0737 Unidad de Excelencia “María de Maeztu”-Centro de Astrobiología (CSIC-INTA). C.G.-C. is supported by predoctoral contract PRE2018-083422 from MCIU. B.M.-G. is supported by predoctoral contract PFIS FI19/00119 from Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo), cofinanced by Fondo Social Europeo (FSE). http://hdl.handle.net/11351/6755 Virus de l'hepatitis C Resistència als medicaments Virus - Reproducció DISEASES::Virus Diseases::Hepatitis, Viral, Human::Hepatitis C Other subheadings::Other subheadings::Other subheadings::Other subheadings::/virology PHENOMENA AND PROCESSES::Microbiological Phenomena::Drug Resistance, Microbial::Drug Resistance, Viral PHENOMENA AND PROCESSES::Microbiological Phenomena::Virus Physiological Phenomena::Virus Replication ENFERMEDADES::virosis::hepatitis viral humana::hepatitis C Otros calificadores::Otros calificadores::Otros calificadores::Otros calificadores::/virología FENÓMENOS Y PROCESOS::fenómenos microbiológicos::farmacorresistencia microbiana::farmacorresistencia viral FENÓMENOS Y PROCESOS::fenómenos microbiológicos::fenómenos fisiológicos de los virus::replicación viral Population Disequilibrium as Promoter of Adaptive Explorations in Hepatitis C Virus