Open AccessGuanosine inhibits hepatitis C virus replication and increases indel frequencies, associated with altered intracellular nucleotide pools
Author(s) -
Rosario Sabariegos,
Ana María Ortega-Prieto,
Luis Díaz-Martínez,
Ana Grande-Pérez,
Carlos GarcíaCrespo,
Isabel Gallego,
Ana Isabel de Ávila,
Laura Albentosa-González,
María Eugenia Soria,
Pablo Gastaminza,
Esteban Domingo,
Celia Perales,
Antonio Más
Publication year - 2022
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1010210
Subject(s) - ns5b , rna polymerase , polymerase , biology , guanosine , rna dependent rna polymerase , viral replication , hepatitis c virus , rna , virology , virus , nucleotide , microbiology and biotechnology , biochemistry , enzyme , gene , hepacivirus
In the course of experiments aimed at deciphering the inhibition mechanism of mycophenolic acid and ribavirin in hepatitis C virus (HCV) infection, we observed an inhibitory effect of the nucleoside guanosine (Gua). Here, we report that Gua, and not the other standard nucleosides, inhibits HCV replication in human hepatoma cells. Gua did not directly inhibit the in vitro polymerase activity of NS5B, but it modified the intracellular levels of nucleoside di- and tri-phosphates (NDPs and NTPs), leading to deficient HCV RNA replication and reduction of infectious progeny virus production. Changes in the concentrations of NTPs or NDPs modified NS5B RNA polymerase activity in vitro , in particular de novo RNA synthesis and template switching. Furthermore, the Gua-mediated changes were associated with a significant increase in the number of indels in viral RNA, which may account for the reduction of the specific infectivity of the viral progeny, suggesting the presence of defective genomes. Thus, a proper NTP:NDP balance appears to be critical to ensure HCV polymerase fidelity and minimal production of defective genomes.