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bioRxiv · 10.1101/2024.03.11.584367

Exploring the therapeutic potential of defective interfering particles in reducing the replication of SARS-CoV-2

Locke, M.·Grebennikov, D.·Sazonov, I.·Lopez-Garcia, M.·Loguinova, M.·Meyerhan, A.·Bocharov, G.·Molina-Paris, C.
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Abstract

SARS-CoV-2 still presents a global threat to human health due to the continued emergence of new strains and waning immunity amongst vaccinated populations. Therefore, it is still relevant to investigate potential therapeutics, such as therapeutic interfering particles (TIPs). Mathematical and computational modelling are valuable tools to study viral infection dynamics for predictive analysis. Here, we expand on the previous work by Grebennikov et al. (2021) on SARS-CoV-2 intra-cellular replication dynamics to include defective interfering particles (DIPs) as potential therapeutic agents. We formulate a deterministic model that describes the replication of wild-type (WT) SARS-CoV-2 virus in the presence of DIPs. Sensitivity analysis of parameters to several model outputs is employed to inform us on those parameters to be carefully calibrated from experimental data. We then study the effects of co-infection on WT replication and how DIP dose perturbs the release of WT viral particles. Furthermore, we provide a stochastic formulation of the model that is compared to the deterministic one. These models could be further developed into population-level models or used to guide the development and dose of TIPs. Author summarySARS-CoV-2 continues to evolve, with new strains or sub-strains being identified thanks to efforts to monitor the virus. Consequently, new strains threaten human health as current vaccinations may not adequately protect against future strains. It is therefore important to understand the roles that additional therapeutics could play in protecting against these future strains. Therapeutic interfering particles (TIPs), otherwise referred to as defective interfering particles (DIPs), could provide an additional treatment option against future strains. Previous models have examined the role of DIPs at the within-host level during co-infection with wild-type virus, but have paid little attention to intra-cellular dynamics. Here we extend the previous intra-cellular replication model of SARS-CoV-2 by Grebennikov et al. (2021) to include co-infection of WT virus with DIPs. We show that DIPs lead to a reduction in the WT virus in a dose-dependent manner, with higher doses leading to up to 10-fold reduction in total WT virus released from a cell depending on the multiplicity of infection (MOI). We find these results to be consistent for both deterministic and stochastic formulations of the model. Our approaches could be developed into a within-host model or population-level model, which could then be used to guide therapeutic DIP doses.

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Locke, M., Grebennikov, D., Sazonov, I., Lopez-Garcia, M., Loguinova, M., Meyerhan, A., Bocharov, G., Molina-Paris, C.. 2024-03-11. Exploring the therapeutic potential of defective interfering particles in reducing the replication of SARS-CoV-2. https://doi.org/10.1101/2024.03.11.584367

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