Quasineutral multistability in an epidemiological-like model for defective-helper betacoronavirus infection in cell cultures

Abstract

It is well known that, during replication, RNA viruses spontaneously generate defective viral genomes (DVGs). DVGs are unable to complete an infectious cycle autonomously, and depend on coinfection with a helper wild-type virus (HV) for their replication and/or transmission. The study of the dynamics arising from a HV and its DVGs has been a longstanding question in virology. It has been shown that DVGs can modulate HV replication and, depending on the strength of interference, result in HV extinctions or self-sustained persistent fluctuations. Extensive experimental work has provided mechanistic explanations for DVG generation and compelling evidences of HV-DVGs virus coevolution. Some of these observations have been captured in mathematical models. Here, we develop and investigate an epidemiological-like mathematical model specifically designed to study the dynamics of betacoronavirus in cell cultures experiments. The dynamics of the model is governed by several degenerate normally hyperbolic invariant manifolds given by quasineutral planes - i.e. filled by equilibrium points. Three different quasineutral planes have been identified depending on parameters and involving: (i) persistence of HV and DVGs; (\emph{ii}) persistence of non-infected cells and DVG-infected cells; and (iii) persistence of DVG-infected cells and DVGs. Sensitivity analyses indicate that model dynamics largely depend on the maximum burst size ($B$), and both the production rate ($β$) and replicative advantage ($δ$) of DVGs. Finally, the model has been fitted to single-passage experimental data using artificial intelligence and key virological parameters have been estimated.