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

  • Molecular Biophysics
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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.

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Authors and Affiliations

  1. Institute of Cytology and Genetics, Siberian Branch, Russian Academy of Sciences, Novosibirsk, 630090, Russia

    N. V. Ivanisenko, E. L. Mishchenko, I. R. Akberdin, P. S. Demenkov, V. A. Likhoshvai, N. A. Kolchanov & V. A. Ivanisenko

  2. St. Petersburg State Polytechnic University, St. Petersburg, 195251, Russia

    K. N. Kozlov, D. I. Todorov, M. G. Samsonova & A. M. Samsonov

  3. The Ioffe Physical Technical Institute of the Russian Academy of Sciences, St.Petersburg, 194021, Russia

    A. M. Samsonov

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  1. N. V. Ivanisenko
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  2. E. L. Mishchenko
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  4. P. S. Demenkov
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  5. V. A. Likhoshvai
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  6. K. N. Kozlov
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  8. M. G. Samsonova
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  9. A. M. Samsonov
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Correspondence to N. V. Ivanisenko.

Additional information

Original Russian Text © N.V. Ivanisenko, E.L. Mishchenko, I.R. Akberdin, P.S. Demenkov, V.A. Likhoshvai, K.N. Kozlov, D.I. Todorov, M.G. Samsonova, A.M. Samsonov, N.A. Kolchanov, V.A. Ivanisenko, 2013, published in Biofizika, 2013, Vol. 58, No. 5, pp. 758–774.

Editor’s Note: I certify that this is a closest equivalent of the original publication with all its factual statements and terminology, phrasing and style; English title and Abstract provided by authors. A.G.

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Ivanisenko, N.V., Mishchenko, E.L., Akberdin, I.R. et al. Replication of the subgenomic hepatitis C virus replicon in the presence of the NS3 protease inhibitors: a stochastic model. BIOPHYSICS 58, 592–606 (2013). https://doi.org/10.1134/S0006350913050059

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  • DOI: https://doi.org/10.1134/S0006350913050059

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