A model for intracellular trafficking of adenoviral vectors.
Here we develop an integrative computational framework to model biophysical processes involved in viral gene delivery. The model combines reaction-diffusion-advection equations that describe intracellular trafficking with kinetic equations that describe transcription and translation of the exogenous DNA. It relates molecular-level trafficking events to whole-cell distribution of viruses. The approach makes use of the current understanding of cellular processes and data from single-particle single-cell imaging experiments. The model reveals two important parameters that characterize viral transport at the population level, namely, the effective velocity, V(eff), and the effective diffusion coefficient, D(eff). V(eff) measures virus's net movement rate and D(eff) represents the total dispersion rate. We employ the model to study the influence of microtubule-mediated movements on nuclear targeting and gene expression of adenoviruses of type 2 and type 5 in HeLa and A549 cells. Effects of microtubule organization and the presence of microtubule-destabilizing drugs on viral transport were analyzed and quantified. Model predictions agree well with experimental data available in literature. The paper serves as a guide for future theoretical and experimental efforts to understand viral gene delivery.
Department of Chemical Engineering, University of California, Santa Barbara, California 93106, USA.
Anh-Tuan
AT
Dinh
Theo
T
Theofanous
Samir
S
Mitragotri
D000256:Adenoviridae / Q000235:genetics*; D001692:Biological Transport; D001703:Biophysics / Q000379:methods*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003599:Cytoskeleton; D003600:Cytosol / Q000378:metabolism; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D008954:Models, Biological; D015233:Models, Statistical; D008962:Models, Theoretical; D015739:Nocodazole / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry; D014176:Protein Biosynthesis; D013997:Time Factors; D014158:Transcription, Genetic
D011108:Polymers; D015739:Nocodazole