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Replication of the subgenomic hepatitis C virus replicon in the presence of the NS3 protease inhibitors: a stochastic model

Content Provider	Springer Nature Link
Author	Ivanisenko, N. V. Mishchenko, E. L. Akberdin, I. R. Demenkov, P. S. Likhoshvai, V. A. Kozlov, K. N. Todorov, D. I. Samsova, M. G. Samsov, A. M. Kolchav, N. A. Ivanisenko, V. A.
Copyright Year	2013
Abstract	The hepatitis C virus (HCV) belongs to Flaviviridae family and causes hazardous liver diseases leading frequently to cirrhosis and hepatocellular carcinoma. HCV is able to rapidly acquire drug resistance and for this reason there is currently no effective anti-HCV therapy in spite of appearance of new potential drugs. Mathematical models are relevant to predict the efficacy of potential drugs against virus or host targets. One of the promising targets for development of new drugs is the viral NS3 protease. Here we developed a stochastic model of the subgenomic HCV replicon replication in Huh-7 cells and in the presence of the NS3 protease inhibitors. Along with consideration of the stochastic nature of the subgenomic HCV replicon replication, the model takes into account the existence and generation of main NS3 protease drug resistant mutants, namely BILN-2061 (A156T, D168V, R155Q), VX-950 (A156S, A156T, T54A) and SCH-503034 (A156T, A156S, T54A). The model reproduces well the viral RNA kinetics in the cell from the moment of the subgenomic HCV replicon transfection to steady state, as well as the viral RNA suppression kinetics in the presence of NS3 protease inhibitors BILN-2061, VX-950 and SCH-503034. We showed that the resistant mutants should be taken into account for the correct description of biphasic kinetics of the viral RNA suppression. The mutants selected in the presence of different inhibitor concentrations have maximal replication capacity in the given inhibitor concentration range. Our model can be used to interpret the results of the new anti-HCV drug testing in replicon systems, as well as to predict the efficacy of new potential drugs and optimize the mode of their use.
Starting Page	592
Ending Page	606
Page Count	15
File Format	PDF
ISSN	00063509
Journal	Biophysics
Volume Number	58
Issue Number	5
e-ISSN	15556654
Language	English
Publisher	Springer US
Publisher Date	2014-02-07
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	hepatitis C virus subgenomic HCV replicon mathematical modeling stochastic model drug-resistant mutants NS3 protease inhibitors drug efficacy Biophysics and Biological Physics
Content Type	Text
Resource Type	Article
Subject	Biophysics

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