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Viruses 2017, 9(10), 282; doi:10.3390/v9100282

3D Spatially Resolved Models of the Intracellular Dynamics of the Hepatitis C Genome Replication Cycle

1
Dipartimento di Scienze Matematiche (DISMA) “G.L. Lagrange”, Politecnico di Torino, Corso Duca degli Abruzzi, 24, 10129 Torino (TO), Italy
2
Goethe Center for Scientific Computing (G-CSC), Goethe Universität Frankfurt, Kettenhofweg 139, 60325 Frankfurt am Main, Germany
3
Applied Mathematics and Computational Science, Computer, Electrical and Mathematical Science and Engineering Division, King Abdullah University of Science and Technology, KAUST, Thuwal 23955, Saudi Arabia
4
Medivir AB, Department of Biology, Huddinge 141 22, Sweden
5
Department of Medicine, Institute for Biostatistics and Mathematic Modeling, Goethe Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 31 July 2017 / Revised: 21 September 2017 / Accepted: 29 September 2017 / Published: 30 September 2017
(This article belongs to the Special Issue Mathematical Modeling of Viral Infections)
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Abstract

Mathematical models of virus dynamics have not previously acknowledged spatial resolution at the intracellular level despite substantial arguments that favor the consideration of intracellular spatial dependence. The replication of the hepatitis C virus (HCV) viral RNA (vRNA) occurs within special replication complexes formed from membranes derived from endoplasmatic reticulum (ER). These regions, termed membranous webs, are generated primarily through specific interactions between nonstructural virus-encoded proteins (NSPs) and host cellular factors. The NSPs are responsible for the replication of the vRNA and their movement is restricted to the ER surface. Therefore, in this study we developed fully spatio-temporal resolved models of the vRNA replication cycle of HCV. Our simulations are performed upon realistic reconstructed cell structures—namely the ER surface and the membranous webs—based on data derived from immunostained cells replicating HCV vRNA. We visualized 3D simulations that reproduced dynamics resulting from interplay of the different components of our models (vRNA, NSPs, and a host factor), and we present an evaluation of the concentrations for the components within different regions of the cell. Thus far, our model is restricted to an internal portion of a hepatocyte and is qualitative more than quantitative. For a quantitative adaption to complete cells, various additional parameters will have to be determined through further in vitro cell biology experiments, which can be stimulated by the results deccribed in the present study. View Full-Text
Keywords: computational virology; hepatitis C virus (HCV); viral dynamics; within-host viral modelling; mathematical models of viral RNA cycle; 3D spatio-temporal resolved mathematical models; realistic geometries; (surface) partial differential equations; Finite Volumes; massively parallel multigrid solvers computational virology; hepatitis C virus (HCV); viral dynamics; within-host viral modelling; mathematical models of viral RNA cycle; 3D spatio-temporal resolved mathematical models; realistic geometries; (surface) partial differential equations; Finite Volumes; massively parallel multigrid solvers
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MDPI and ACS Style

Knodel, M.M.; Reiter, S.; Targett-Adams, P.; Grillo, A.; Herrmann, E.; Wittum, G. 3D Spatially Resolved Models of the Intracellular Dynamics of the Hepatitis C Genome Replication Cycle. Viruses 2017, 9, 282.

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