Ribavirin inhibition of cell-culture infectious hepatitis C genotype 1-3 viruses is strain-dependent
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Ribavirin inhibition of cell-culture infectious hepatitis C genotype 1-3 viruses is strain-dependent. / Mejer, Niels; Galli, Andrea; Ramirez, Santseharay; Fahnøe, Ulrik; Benfield, Thomas; Bukh, Jens.
In: Virology, Vol. 540, 2020, p. 132-140.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Ribavirin inhibition of cell-culture infectious hepatitis C genotype 1-3 viruses is strain-dependent
AU - Mejer, Niels
AU - Galli, Andrea
AU - Ramirez, Santseharay
AU - Fahnøe, Ulrik
AU - Benfield, Thomas
AU - Bukh, Jens
PY - 2020
Y1 - 2020
N2 - Ribavirin remains relevant for successful treatment of chronic hepatitis C virus (HCV) infections in low-income settings, as well as for therapy of difficult-to-treat HCV patients. We studied the effect of ribavirin against cell-culture adapted HCV of genotypes 1, 2 and 3, representing ~80% of global infections. TNcc(1a) was the most sensitive to ribavirin, while J6/JFH1(2a) was the most resistant. EC50s ranged from 21 μM (95%CI: 20–22 μM) to 189 μM (95%CI: 173–207 μM). Substitutions at position 415 of NS5B resulted in little or no change to ribavirin sensitivity (0.7–0.9 fold) but conferred moderate drug resistance during extended treatment of genotype 1 (1.8-fold). NS5A and NS5B sequences could alter ribavirin sensitivity 2-4-fold, although their contribution was not simply additive. Finally, we detected limited accumulation of mutations associated with ribavirin treatment. Our findings show that the antiviral effect of ribavirin on HCV is strain-dependent and is influenced by the specific sequence of multiple HCV nonstructural proteins.
AB - Ribavirin remains relevant for successful treatment of chronic hepatitis C virus (HCV) infections in low-income settings, as well as for therapy of difficult-to-treat HCV patients. We studied the effect of ribavirin against cell-culture adapted HCV of genotypes 1, 2 and 3, representing ~80% of global infections. TNcc(1a) was the most sensitive to ribavirin, while J6/JFH1(2a) was the most resistant. EC50s ranged from 21 μM (95%CI: 20–22 μM) to 189 μM (95%CI: 173–207 μM). Substitutions at position 415 of NS5B resulted in little or no change to ribavirin sensitivity (0.7–0.9 fold) but conferred moderate drug resistance during extended treatment of genotype 1 (1.8-fold). NS5A and NS5B sequences could alter ribavirin sensitivity 2-4-fold, although their contribution was not simply additive. Finally, we detected limited accumulation of mutations associated with ribavirin treatment. Our findings show that the antiviral effect of ribavirin on HCV is strain-dependent and is influenced by the specific sequence of multiple HCV nonstructural proteins.
KW - Antivirals
KW - Cell culture
KW - Genotype
KW - HCV
KW - Hepatitis C virus
KW - In vitro
KW - Mechanism
KW - Polymerase
KW - Ribavirin
U2 - 10.1016/j.virol.2019.09.014
DO - 10.1016/j.virol.2019.09.014
M3 - Journal article
C2 - 31778898
AN - SCOPUS:85075387173
VL - 540
SP - 132
EP - 140
JO - Virology
JF - Virology
SN - 0042-6822
ER -
ID: 235589980