The pandemic spawned by the SARS-CoV-2 virus, the etiological agent of COVID-19, has had devastating worldwide repercussions. Numerous complementary strategies must be taken to address this issue and to ameliorate the consequences, including the use of therapeutics. To facilitate identification and development of therapeutics, it is critical to gain a better understanding of the fundamental viral dynamics of SARS-CoV-2. Such insight will allow for the rapid initial in silico assessment of therapeutics, including identification of potential high value molecules, as well as determination of optimal treatment strategies. In this work, a systems virology approach was used to develop models of the intracellular kinetics of SARS-CoV-2. Using a mass action kinetics assumption, systems of ordinary differential equations were implemented to generate multiple models of varying subcellular resolution. Parameters were estimated based on data from the literature. Network topology was determined using the current understanding of SARS-CoV-2 molecular virology. Stability analysis was carried out to facilitate model discrimination. Results of the best performing model showed qualitative behavior similar to that seen in experimental studies. The model, however, also provided insight into the behavior of molecular components whose dynamics have not been experimentally explored in detail. Unsurprisingly, the model indicated a dramatic rise in the amount of viral genome upon initiation of infection. As would be expected, a concomitant boost in the level of viral proteins was also observed. Interestingly, and somewhat surprisingly, in a relatively short period of time, the amount of viral genome within the cell began to decrease rapidly to a new much lower level. However, the level of genome was sufficiently high enough that, while the rate of net viral protein production slowed down significantly, overall viral protein levels continued to increase. It appeared that the primary reason that the viral genome level decreased was that they were being packaged for virion secretion rather than being used for viral protein synthesis. Ultimately, the initial rapid “priming” of the viral production system was sufficient enough such that, after reaching a critical point, viral resources were able to be primarily allocated towards virion release while the viral protein synthesis machinery continued growing, albeit at a slower rate and at lower overall levels.

Intracellular kinetic modeling of SARS-CoV-2 for development of therapeutic treatment strategies

ACS Spring 2022

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