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To evaluate the effects of HCV NS5B amino acid substitutions on treatment outcome in Ledipasvir (LDV)/Sofosbuvir (SOF) for Japanese patients with genotype 1b HCV infection, NS5B sequences were examined in i) seven patients experiencing virologic failure after LDV/SOF in real-world practice, ii) 109 SOF-naïve patients, iii) 165 patients enrolled in Phase-3 LDV/SOF trial. A218S and C316N were detected in all patients with viral relapse; the percentages of these substitutions in SOF-naïve patients were 64.2% and 55.0%, respectively. Genotype 1b HCV strains with NS5B-C316N mutation were located in the leaves different from those in which HCV strains without such substitutions were present on the phylogenetic tree. Structural modeling revealed that amino acid 218 was located on the surface of the NTP tunnel. Free energy analysis based on molecular dynamics simulations demonstrated that the free energy required to pass through the tunnel was larger for triphosphate SOF than for UTP in NS5B polymerase carrying A218S, but not in wild-type. However, no susceptibility change was observed for these substitutions to SOF in replicon assay. Furthermore, the SVR rate was 100% in patients enrolled the Phase-3 trial. In conclusion, NS5B A218S and C316N were detected in all patients who relapsed following LDV/SOF in real-world practice. These substitutions did not impact the overall SVR rate after LDV/SOF, however, further studies are needed to elucidate the impact of these substitutions.
Pubmed ID: 29892096
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A user-sponsored molecular visualization software system on an open-source foundation. The software has the capabilities to view, render, animate, export, present and develop three dimensional molecular structures.
View all literature mentionsSoftware package of molecular simulation programs. It is distributed into AmberTools15 and Amber14. AmberTools15 is a software package which can carry out complete molecular dynamics simulations with either explicit water or generalized Born solvent models. It is distributed in source code format and must be compiled in order to be used. Amber14 builds on AmberTools15 by adding the pmemd program, which provides better performance on multiple CPUs and dramatic speed improvements on GPUs compared to sander (molecular dynamics). GPU info, manuals, and tutorials are available on the website.
View all literature mentionsMiSeq System offers wide range of sequencing applications. Capable of automated paired end reads and up to 15 Gb per run, delivering over 600 bases of sequence data per read. The library prep kits are optimized for variety of applications, including targeted gene, small genome, and amplicon sequencing, 16S metagenomics.
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