Mathematical Model for Suppression of Subgenomic Hepatitis C Virus Rna Replication in Cell Culture

Abstract

A mathematical model for suppression of the hepatitis C virus RNA replicon replication in Huh-7 cell culture in the presence of potential drugs was built. There was a good agreement between the experimental and theoretical kinetic data for the decrease in the level of viral RNA in the cell in the presence of the competitive HCV NS3 protease inhibitor. Using the model, we verified the estimates for the efficiency of the effect of potential drugs on replication of viral RNA and viral protein processing. It was demonstrated that the tested drugs are most efficient at the replication step of viral RNA. The efficiency of the combined action of real and putative inhibitors target on the host and viral proteins was also studied. It was found that the action of the inhibitor at low concentrations on the host factors considerably enhances the suppressive effect on viral RNA replication in the presence of even the low affine NS3 protease inhibitors. The developed mathematical model may serve as a tool for the evaluation of the efficiency of potential drugs on the HCV genome.

Replication Vesicles are Load- and Choke-Points in the Hepatitis C Virus Lifecycle

“…In contrast to previous models [24], [25], [26] we were not only interested in studying steady state replication in stable replicon cell lines, but specifically addressed the highly dynamic initial phase after RNA genome delivery into the host cell. We therefore performed quantitative, time-resolved measurements of viral protein translation as well as strand-specific viral RNA concentrations in two distinct Huh-7 derived cell lines, exhibiting a vastly different permissiveness for HCV RNA replication [32].…”

“…A thorough quantitative analysis of persistent subgenomic replicons in Huh-7 cells [10] led to the development of a first mathematical model of intracellular steady state RNA replication [24]. Further models addressed the effect of potential drugs on viral replication [25] or included the production of virus particles [26], [27]. However, all published models were solely based on measurements of steady state replication.…”

A New Stochastic Model for Subgenomic Hepatitis C Virus Replication Considers Drug Resistant Mutants

“…The model allows to correctly describe viral RNA replication in the absence of inhibitors and establishment of the steady state after transfection. We proposed a mathematical model of the suppression of the subgenomic hepatitis C virus RNA replication [53]. This model was aimed to evaluate the effect of drugs on viral RNA replication.…”

“…Binder et al [54] recently suggested extended model of Dahari [52] in particular by inclusion of generalized cell factor like in Mischenko et al [53].The model made it possible to explain the differences in HCV permissiveness in different cell lines.…”

“…MacLean and co-authors [56], also focused on the HCV full life cycle, including translation, replication and assembly. In contrast to the model from Mishchenko et al [53], none of these models included the action of drugs on viral or cellular targets and none of them were used to describe viral RNA kinetics in the presence of inhibitors. However, the model from Mishchenko et al [53] failed to simulate the dynamics of inhibitor action for time intervals longer than 3 days.…”