title: A new stochastic model for subgenomic hepatitis C virus replication considers drug resistant mutants.
abstract: As an RNA virus, hepatitis C virus (HCV) is able to rapidly acquire drug resistance, and for this reason the design of effective anti-HCV drugs is a real challenge. The HCV subgenomic replicon-containing cells are widely used for experimental studies of the HCV genome replication mechanisms, for drug testing in vitro and in studies of HCV drug resistance. The NS3/4A protease is essential for virus replication and, therefore, it is one of the most attractive targets for developing specific antiviral agents against HCV. We have developed a stochastic model of subgenomic HCV replicon replication, in which the emergence and selection of drug resistant mutant viral RNAs in replicon cells is taken into account. Incorporation into the model of key NS3 protease mutations leading to resistance to BILN-2061 (A156T, D168V, R155Q), VX-950 (A156S, A156T, T54A) and SCH 503034 (A156T, A156S, T54A) inhibitors allows us to describe the long term dynamics of the viral RNA suppression for various inhibitor concentrations. We theoretically showed that the observable difference between the viral RNA kinetics for different inhibitor concentrations can be explained by differences in the replication rate and inhibitor sensitivity of the mutant RNAs. The pre-existing mutants of the NS3 protease contribute more significantly to appearance of new resistant mutants during treatment with inhibitors than wild-type replicon. The model can be used to interpret the results of anti-HCV drug testing on replicon systems, as well as to estimate the efficacy of potential drugs and predict optimal schemes of their usage.
authors.affiliation: Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
authors.forename: Nikita V
authors.initials: NV
authors.lastname: Ivanisenko
authors.affiliation: Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
authors.forename: Elena L
authors.initials: EL
authors.lastname: Mishchenko
authors.affiliation: Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
authors.forename: Ilya R
authors.initials: IR
authors.lastname: Akberdin
authors.affiliation: Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
authors.forename: Pavel S
authors.initials: PS
authors.lastname: Demenkov
authors.affiliation: Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
authors.forename: Vitaly A
authors.initials: VA
authors.lastname: Likhoshvai
authors.affiliation: Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia.
authors.forename: Konstantin N
authors.initials: KN
authors.lastname: Kozlov
authors.affiliation: Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia; Chebyshev Laboratory, St. Petersburg State University, St. Petersburg, Russia.
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Todorov
authors.affiliation: Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia; Theoretical Department, Ioffe Physical-Technical Institute of the Russian Academy of Sciences, St.Petersburg, Russia.
authors.forename: Vitaly V
authors.initials: VV
authors.lastname: Gursky
authors.affiliation: Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Samsonova
authors.affiliation: Department of Computational Biology, St. Petersburg State Polytechnical University, St. Petersburg, Russia; Theoretical Department, Ioffe Physical-Technical Institute of the Russian Academy of Sciences, St.Petersburg, Russia.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Samsonov
authors.affiliation: Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Clausznitzer
authors.affiliation: Institute for Medical Informatics and Biometry, Technische Universität Dresden, Dresden, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.affiliation: Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.
authors.forename: Nikolay A
authors.initials: NA
authors.lastname: Kolchanov
authors.affiliation: Department of Systems Biology, Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia; PB-soft Llc, Novosibirsk, Russia.
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Ivanisenko
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D047028:Macrocyclic Compounds / Q000494:pharmacology; D015233:Models, Statistical; D009842:Oligopeptides / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012367:RNA, Viral / Q000235:genetics*; D012093:Replicon; D013269:Stochastic Processes; D013844:Thiazoles / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D014779:Virus Replication / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D047028:Macrocyclic Compounds; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D011804:Quinolines; D012367:RNA, Viral; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C479555:BILN 2061; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide