A mathematical model of the trafficking of acid-dependent enveloped viruses: Application to the binding, uptake, and nuclear accumulation of baculovirus

Abstract

A quantitative understanding of virus trafficking would be useful in treating viral‐mediated diseases, developing protocols for viral gene therapy, designing infection regimens for viral expression systems, and optimizing vaccine and recombinant protein production. Here, we present a mathematical model of the attachment, internalization, endosomal fusion, lysosomal routing, and nuclear accumulation of baculovirus in SF21 insect cells. The model accounts for multivalent bond formation of the virus with cell surface receptors. The model mimics accurately the experimental trafficking dynamics of the virus at both low and high virion to cell ratios, and estimates a receptor number of 11,000 per cell. A significant amount of virus was degraded intracellularly. Independent of the virion to cell ratio, half of the internalized virus was degraded with the rest accumulating in the nucleus. The formalism used in the model may be generally useful for other acid‐dependent enveloped viruses. A subset of the model has been used previously to describe the trafficking of Semliki Forest virus, an acid‐dependent enveloped RNA virus. Two pathways have previously been implicated for the in vitro entry of the budded form of the baculovirus: adsorptive endocytosis and plasma membrane fusion. Experimental evidence is presented which strongly suggests that the physical number of viruses entering by plasma membrane fusion is not significant relative to receptor‐mediated endocytosis. © 1997 John Wiley & Sons, Inc., Biotechnol Bioeng 54: 468–490, 1997.

Modeling the Intracellular Dynamics of Influenza Virus Replication To Understand the Control of Viral RNA Synthesis

“…In the past, modeling has provided valuable insights into the intracellular replication of eukaryotic viruses (10,11,23,34,48). For influenza virus, such a model was previously developed by our group to assess the amount of cellular resources that are consumed by virus replication during cell culture-based vaccine production (55).…”

Production of Recombinant Protein Using the HeLa S3-Vaccinia Virus Expression System: Bioreactor Perfusion and Effects of Post-Infection Temperature

“…A similar phenomenon has been described for baculovirus infection where suspension cultures had higher attachment rates for the virus than monolayer cultures. 23,29) Additionally, in this case, MOIs of 5.0 and 10.0 appeared to increase cell death over MOI 1.0, as indicated by the slightly lower viable cell densities reported at 24 and 48 hpi. These lower viable cell densities might partially explain the lower expression at these higher MOIs.…”

“…Dee et al 23) developed a model for baculovirus-infected insect cells which can be generalized to other acid-dependent enveloped viruses. They found that binding of the virus to the cell receptor was the rate-limiting step.…”

“…16,17) This was not unique to vaccinia; differences between tissue plate culture and suspension culture have been shown in baculovirus/ insect cell studies. 23) Further, lowered temperature during the protein production phase has been shown to be beneficial for both the Semliki Forest Virus expression system 24) and the vaccinia virus expression system in microcarrier based cultures. 17) This may have been due to a reduced cytopathic effect from the virus at y To whom correspondence should be addressed.…”

Host Factors in Viral Life Cycles

“…Until today, most modeling attempts have concentrated on viral dynamics in infected individuals and did not consider specific viral features within single infected cells but rather assumed constant virus production rates. The rapidly increasing knowledge on host-virus cell interactions should now be considered and may substantially extend the few modeling attempts on the single cell level that have been performed [12,13,28,46,53,69,74]. With the inclusion of key regulatory steps in the viral life cycles that are mediated by host components under the conditions of infected cells, the new models may improve our understanding of virus-induced pathogenic processes and help to develop novel treatment regimens.…”