TY - JOUR
T1 - Fitness-Dependent, Mild Mutagenic Activity of Sofosbuvir for Hepatitis C Virus
AU - Martínez-González, Brenda
AU - Gallego, Isabel
AU - Gregori, Josep
AU - Soria, María Eugenia
AU - Somovilla, Pilar
AU - de Ávila, Ana Isabel
AU - García-Crespo, Carlos
AU - Durán-Pastor, Antoni
AU - Briones, Carlos
AU - Gómez, Jordi
AU - Quer, Josep
AU - Domingo, Esteban
AU - Perales, Celia
N1 - Publisher Copyright:
Copyright © 2023 American Society for Microbiology. All Rights Reserved.
PY - 2023/7
Y1 - 2023/7
N2 - The concept of a mild mutagen was coined to describe a minor mutagenic activity exhibited by some nucleoside analogues that potentiated their efficacy as antiretroviral agents. In the present study, we report the mild mutagen activity of sofosbuvir (SOF) for hepatitis C virus (HCV). Serial passages of HCV in human hepatoma cells, in the presence of SOF at a concentration well below its cytotoxic concentration 50 (CC50) led to pre-extinction populations whose mutant spectra exhibited a significant increase of C!U transitions, relative to populations passaged in the absence of SOF. This was reflected in an increase in several diversity indices that were used to characterize viral quasispecies. The mild mutagenic activity of SOF was largely absent when it was tested with isogenic HCV populations that displayed high replicative fitness. Thus, SOF can act as a mild mutagen for HCV, depending on HCV fitness. Possible mechanisms by which the SOF mutagenic activity may contribute to its antiviral efficacy are discussed.
AB - The concept of a mild mutagen was coined to describe a minor mutagenic activity exhibited by some nucleoside analogues that potentiated their efficacy as antiretroviral agents. In the present study, we report the mild mutagen activity of sofosbuvir (SOF) for hepatitis C virus (HCV). Serial passages of HCV in human hepatoma cells, in the presence of SOF at a concentration well below its cytotoxic concentration 50 (CC50) led to pre-extinction populations whose mutant spectra exhibited a significant increase of C!U transitions, relative to populations passaged in the absence of SOF. This was reflected in an increase in several diversity indices that were used to characterize viral quasispecies. The mild mutagenic activity of SOF was largely absent when it was tested with isogenic HCV populations that displayed high replicative fitness. Thus, SOF can act as a mild mutagen for HCV, depending on HCV fitness. Possible mechanisms by which the SOF mutagenic activity may contribute to its antiviral efficacy are discussed.
KW - antiviral agent
KW - lethal defection
KW - ultradeep sequencing
KW - viral fitness
KW - viral quasispecies
KW - Hepacivirus/genetics
KW - Humans
KW - Sofosbuvir/pharmacology
KW - Genotype
KW - Treatment Outcome
KW - Mutagens/pharmacology
KW - Hepatitis C/drug therapy
KW - Antiviral Agents/pharmacology
KW - Hepatitis C, Chronic/drug therapy
KW - Drug Therapy, Combination
KW - Ribavirin/therapeutic use
UR - http://www.scopus.com/inward/record.url?scp=85164845846&partnerID=8YFLogxK
U2 - 10.1128/AAC.00394-23
DO - 10.1128/AAC.00394-23
M3 - Article
C2 - 37367486
AN - SCOPUS:85164845846
SN - 0066-4804
VL - 67
SP - e0039423
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 7
M1 - e00394-23
ER -
