How does the virus move within a cell?: a comparative model of viral diffusion and active transport and their impact on the dynamics of viral infection

Avni Choksi

doi:10.17918/etd-4232

Models of viral infection at the cellular level have been simulated in terms of the viral dynamics between cells. There are few current models that simulate and describe the interactions of the viral infection within the cell, explicitly the transportation of viruses in the cell to the nucleus for viral replication. The goal of the model is to simulate the ability of a virus to travel from the membrane, to the nucleus and back. Also, to identify which cellular determinants are important for viral transportation. I created a 2D stochastic agent based model of a single cell in which every entity is a virus. The cellular components modeled in my simulation are the nucleus and a network of microtubules which is connect to the microtubule-organizing center(MTOC), each of which allowed movement only in one direction (from viral entry to the nucleus and to the other side of the cell). Depending on the geographical position in the cell, each virus can move, degrade or if adjacent to the microtubule, either latch on or unbind. Viruses could only proliferate in the nucleus. I hypothesized that using only simple diffusion in the cytoplasm; viruses would take a longer time to reach the nucleus and be unable to properly proliferate. Rates of diffusion in the cytoplasm, movement along the microtubules, proliferation, and degradation were based on studies of adeno-associated virus (AAV). I altered the level of infection (number of viruses that pass the membrane), the initial viral location inside the cell membrane, the density of microtubules and the location of the MTOC. I found that without microtubules, viruses effectively reach the nucleus at a slower time than with microtubules. Furthermore, without microtubules viruses reach the nucleus at all at a lesser probability. The model with microtubules, nearly 100% of simulations resulted in at least one virus reaching the nucleus, while viruses reached the nucleus only ~ %30 of simulations without microtubules. In all instances the ability to infect goes up with viral load and microtubule density. The speed of viruses leaving the cell from the nucleus is also enhanced and is ~3-5 times faster with microtubules than without them. Two confusing findings were also discovered- (1) the numbers of viruses that reached the nucleus in microtubule cells was low and only at the start of the simulation. (2) In all cases, hardly any viruses proliferated, the simulations ended with total virus death. I believe these are the results of artifacts in my model that will be addressed in future work as well as address the for (1) microtubules to direct viruses in both directions (i.e. viruses to move back and forth around the nucleus); (2) simulations with different levels of permeability in the nucleus that will ensure viruses remain there and proliferate. However, my currant findings show clearly that an important limiting state of successful infection is the movement within the cell and the ability of the virus to utilize the microtubules to do so. Potentially, the issue of transport holds more importance than entering the cell for successful viral infection suggesting a new avenue for viral therapies focused on inhibiting the viral attachment to microtubules.

How does the virus move within a cell?: a comparative model of viral diffusion and active transport and their impact on the dynamics of viral infection

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How does the virus move within a cell?: a comparative model of viral diffusion and active transport and their impact on the dynamics of viral infection

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