Efficient Simulation of Viral Transduction and Propagation for Biomanufacturing

Abstract

Viral transduction is a main route for gene transfer to producer cells in biomanufacturing. Designing a transduction-based biomanufacturing process poses significant challenges, due to the complex dynamics of viral infection and virus-host interaction. This article introduces a software toolkit composed of a multiscale model and an efficient numeric technique that can be leveraged for determining genetic and process designs that optimize transduction-based biomanufacturing platforms. Viral transduction and propagation for up to two viruses simultaneously can be simulated through the model, considering viruses in either lytic or lysogenic stage, during batch, perfusion, or continuous operation. The model estimates the distribution of the viral genome(s) copy number in the cell population, which is an indicator of transduction efficiency and viral genome stability. The infection age distribution of the infected cells is also calculated, indicating how many cells are in an infection stage compatible with recombinant product expression and/or with viral amplification. The model can also consider the presence in the system of defective interfering particles, which can severely compromise the productivity of biomanufacturing processes. Model benchmarking and validation are demonstrated for case studies on the baculovirus expression vector system and influenza A propagation in suspension cultures. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/587435v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1752f59org.highwire.dtl.DTLVardef@779987org.highwire.dtl.DTLVardef@8d14org.highwire.dtl.DTLVardef@2e4514_HPS_FORMAT_FIGEXP M_FIG C_FIG