Antiviral Effect of Ribavirin against HCV Associated with Increased Frequency of G-to-A and C-to-U Transitions in Infectious Cell Culture Model
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Antiviral Effect of Ribavirin against HCV Associated with Increased Frequency of G-to-A and C-to-U Transitions in Infectious Cell Culture Model. / Galli, Andrea; Mens, Helene; Gottwein, Judith M; Gerstoft, Jan; Bukh, Jens.
I: Scientific Reports, Bind 8, Nr. 1, 4619, 2018.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Antiviral Effect of Ribavirin against HCV Associated with Increased Frequency of G-to-A and C-to-U Transitions in Infectious Cell Culture Model
AU - Galli, Andrea
AU - Mens, Helene
AU - Gottwein, Judith M
AU - Gerstoft, Jan
AU - Bukh, Jens
PY - 2018
Y1 - 2018
N2 - Ribavirin (RBV) is a broad-spectrum antiviral active against a wide range of RNA viruses. Despite having been used for decades in the treatment of chronic hepatitis C virus (HCV) infection, the precise mechanism of action of RBV is unknown. In other viruses, it inhibits propagation by increasing the rate of G-to-A and C-to-U transitions. Here, we utilized the J6/JFH1 HCV cell-culture system to investigate whether RBV inhibits HCV through the same mechanism. Infected Huh7.5 cells were treated with increasing concentrations of RBV or its phosphorylated forms. A fragment of the HCV NS5B-polymerase gene was amplified, cloned, and sequenced to estimate genetic distances. We confirm that the antiviral effect of all three RBV-drug forms on HCV relies on induction of specific transitions (G-to-A and C-to-U). These mutations lead to generation of non-infectious virions, reflected by decreased spread of HCV in cell culture despite relatively limited effect on virus genome titers. Moreover, treatment experiments conducted on a novel Huh7.5 cell line stably overexpressing adenosine kinase, a key enzyme for RBV activation, yielded comparable results. This study indicates that RBV action on HCV in hepatoma cell-culture is exerted through increase in mutagenesis, mediated by RBV triphosphate, and leading to production of non-infectious viruses.
AB - Ribavirin (RBV) is a broad-spectrum antiviral active against a wide range of RNA viruses. Despite having been used for decades in the treatment of chronic hepatitis C virus (HCV) infection, the precise mechanism of action of RBV is unknown. In other viruses, it inhibits propagation by increasing the rate of G-to-A and C-to-U transitions. Here, we utilized the J6/JFH1 HCV cell-culture system to investigate whether RBV inhibits HCV through the same mechanism. Infected Huh7.5 cells were treated with increasing concentrations of RBV or its phosphorylated forms. A fragment of the HCV NS5B-polymerase gene was amplified, cloned, and sequenced to estimate genetic distances. We confirm that the antiviral effect of all three RBV-drug forms on HCV relies on induction of specific transitions (G-to-A and C-to-U). These mutations lead to generation of non-infectious virions, reflected by decreased spread of HCV in cell culture despite relatively limited effect on virus genome titers. Moreover, treatment experiments conducted on a novel Huh7.5 cell line stably overexpressing adenosine kinase, a key enzyme for RBV activation, yielded comparable results. This study indicates that RBV action on HCV in hepatoma cell-culture is exerted through increase in mutagenesis, mediated by RBV triphosphate, and leading to production of non-infectious viruses.
U2 - 10.1038/s41598-018-22620-2
DO - 10.1038/s41598-018-22620-2
M3 - Journal article
C2 - 29545599
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 4619
ER -
ID: 213166470