Examinando por Autor "Llorens Revull, Meritxell"

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Amino acid substitutions associated with treatment failure for Hepatitis C virus infection
(American Society for Microbiology, 2020-12) Soria, María Eugenia; García Crespo, Carlos; Martínez González, Brenda; Vázquez Sirvent, L.; Lobo Vega, Rebeca; Ávila, Ana Isabel de; Gallego, Isabel; Chen, Qian; García Cehic, Damir; Llorens Revull, Meritxell; Briones, C.; Gómez, Jordi; Ferrer Orta, Cristina; Verdaguer, Nuria; Gregori, Josep; Rodríguez Frías, Francisco; Buti, María; Ignacio Esteban, Juan; Domingo, Esteban; Quer, Josep; Perales, Celia; Ministerio de Economía y Competitividad (MINECO); Agencia Estatal de Investigación (AEI); Instituto de Salud Carlos III (ISCIII); Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, España; Centro para el Desarrollo Tecnológico Industrial (CDTI); Fundación Ramón Areces; Banco de Santander; CSIC-INTA - Centro de Astrobiología, CAB; Unidad de Excelencia Científica María de Maeztu Centro de Astrobiología del Instituto Nacional de Técnica Aeroespacial y CSIC, MDM-2017-0737
Despite the high virological response rates achieved with current directly acting antiviral agents (DAAs) against hepatitis C virus (HCV), around 2% to 5% of treated patients do not achieve a sustained viral response. The identification of amino acid substitutions associated with treatment failure requires analytical designs, such as subtype-specific ultradeep sequencing (UDS) methods, for HCV characterization and patient management. Using this procedure, we have identified six highly represented amino acid substitutions (HRSs) in NS5A and NS5B of HCV, which are not bona fide resistance-associated substitutions (RAS), from 220 patients who failed therapy. They were present frequently in basal and posttreatment virus of patients who failed different DAA-based therapies. Contrary to several RAS, HRSs belong to the acceptable subset of substitutions according to the PAM250 replacement matrix. Their mutant frequency, measured by the number of deep sequencing reads within the HCV quasispecies that encode the relevant substitutions, ranged between 90% and 100% in most cases. They also have limited predicted disruptive effects on the three-dimensional structures of the proteins harboring them. Possible mechanisms of HRS origin and dominance, as well as their potential predictive value for treatment response, are discussed.