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

Handle URI:
http://hdl.handle.net/10754/625833
Title:
3D Spatially Resolved Models of the Intracellular Dynamics of the Hepatitis C Genome Replication Cycle
Authors:
Knodel, Markus; Reiter, Sebastian; Targett-Adams, Paul ( 0000-0003-4967-1668 ) ; Grillo, Alfio; Herrmann, Eva; Wittum, Gabriel
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.
KAUST Department:
Applied Mathematics and Computational Science Program; Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Citation:
Knodel M, Reiter S, Targett-Adams P, Grillo A, Herrmann E, et al. (2017) 3D Spatially Resolved Models of the Intracellular Dynamics of the Hepatitis C Genome Replication Cycle. Viruses 9: 282. Available: http://dx.doi.org/10.3390/v9100282.
Publisher:
MDPI AG
Journal:
Viruses
Issue Date:
2-Oct-2017
DOI:
10.3390/v9100282
Type:
Article
ISSN:
1999-4915
Sponsors:
We thank Andreas Vogel, Michael Lampe, Martin Rupp and Konstantinos Xylouris (G-CSC) for technical help and helpful discussions, Wouter van Beerendonk (Huygens SVI, Netherlands) for his very friendly support in Huygens usage, backgrounds, and licensing. The HLRS Stuttgart is acknowledged for the supplied computing time on the Hermit and Hornet super computers [37]. The authors acknowledge the Goethe-University Frankfurt and the Politecnico di Torino for general support and computational resources. This work has been supported in part by the “Fondazione Cassa di Risparmio di Torino” (Italy), through the “La Ricerca dei Talenti” (HR Excellence in Research) programme. The Authors wish to express their sincere thanks to the anonymous Referees for their thorough and critical reviews of our work.
Additional Links:
http://www.mdpi.com/1999-4915/9/10/282
Appears in Collections:
Articles; Applied Mathematics and Computational Science Program; Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorKnodel, Markusen
dc.contributor.authorReiter, Sebastianen
dc.contributor.authorTargett-Adams, Paulen
dc.contributor.authorGrillo, Alfioen
dc.contributor.authorHerrmann, Evaen
dc.contributor.authorWittum, Gabrielen
dc.date.accessioned2017-10-09T09:03:11Z-
dc.date.available2017-10-09T09:03:11Z-
dc.date.issued2017-10-02en
dc.identifier.citationKnodel M, Reiter S, Targett-Adams P, Grillo A, Herrmann E, et al. (2017) 3D Spatially Resolved Models of the Intracellular Dynamics of the Hepatitis C Genome Replication Cycle. Viruses 9: 282. Available: http://dx.doi.org/10.3390/v9100282.en
dc.identifier.issn1999-4915en
dc.identifier.doi10.3390/v9100282en
dc.identifier.urihttp://hdl.handle.net/10754/625833-
dc.description.abstractMathematical 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.en
dc.description.sponsorshipWe thank Andreas Vogel, Michael Lampe, Martin Rupp and Konstantinos Xylouris (G-CSC) for technical help and helpful discussions, Wouter van Beerendonk (Huygens SVI, Netherlands) for his very friendly support in Huygens usage, backgrounds, and licensing. The HLRS Stuttgart is acknowledged for the supplied computing time on the Hermit and Hornet super computers [37]. The authors acknowledge the Goethe-University Frankfurt and the Politecnico di Torino for general support and computational resources. This work has been supported in part by the “Fondazione Cassa di Risparmio di Torino” (Italy), through the “La Ricerca dei Talenti” (HR Excellence in Research) programme. The Authors wish to express their sincere thanks to the anonymous Referees for their thorough and critical reviews of our work.en
dc.publisherMDPI AGen
dc.relation.urlhttp://www.mdpi.com/1999-4915/9/10/282en
dc.rightsThis is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectHepatitis C virus (HCV)en
dc.subjectViral Dynamicsen
dc.subjectFinite Volumesen
dc.subject(Surface) Partial Differential Equationsen
dc.subject3D Spatio-temporal Resolved Mathematical Modelsen
dc.subjectComputational Virologyen
dc.subjectMassively Parallel Multigrid Solversen
dc.subjectMathematical Models Of Viral Rna Cycleen
dc.subjectRealistic Geometriesen
dc.subjectWithin-host Viral Modellingen
dc.title3D Spatially Resolved Models of the Intracellular Dynamics of the Hepatitis C Genome Replication Cycleen
dc.typeArticleen
dc.contributor.departmentApplied Mathematics and Computational Science Programen
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Divisionen
dc.identifier.journalVirusesen
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionDipartimento di Scienze Matematiche (DISMA)en
dc.contributor.institutionGoethe Center for Scientific Computing (G-CSC), Goethe Universität Frankfurt, Kettenhofweg 139, 60325 Frankfurt am Main, Germany.en
dc.contributor.institutionMedivir AB, Department of Biology, Huddinge 141 22, Sweden.en
dc.contributor.institutionDepartment of Medicine, Institute for Biostatistics and Mathematic Modeling, Goethe Universität Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.en
kaust.authorWittum, Gabrielen
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