Intra and inter-cellular modeling of dynamic interaction between Zika virus and its naturally occurring defective viral genomes.

Here we examine in-silico the infection dynamics and interactions of two ZIKV genomes: one is the full-length ZIKV genome (WT) and the other is one of the naturally occurring defective viral genomes (DVG), which can replicate in the presence of WT genome, appears under high MOI passaging conditions and carries a deletion encompassing part of the structural and NS1 protein-coding region. Ordinary differential equations (ODE) were used to simulate the infection of cells by virus particles and intra-cellular replication of the WT and DVG genomes that produces these particles. For each virus passage in Vero and C6/36 cell cultures, rates of the simulated processes were fitted to two types of observations: virus titer data and the assembled haplotypes of the replicate passage samples. We studied the consistency of the model with the experimental data across all passages of infection in each cell type separately, as well as sensitivity of model's parameters. We also determined which simulated processes of the virus evolution are most important for adaptation of the WT and DVG interplay in these two disparate cell culture environments. Our results demonstrate that in majority of passages, the rates of DVG-production are higher in the C6/36 cells compared to Vero cells, which might result in tolerance and therefore drive persistence of the mosquito vector in the context of ZIKV infection. Additionally, the model simulations showed slower accumulation of infected cells under higher activation of the DVG associated processes, which indicates potential role of DVGs in virus attenuation. Importance. One of ideas on lessening Zika pathogenicity is addition of its natural or engineered defective virus genomes (DVG: have no pathogenicity) to the infection pool: DVG is redirecting the wild type (WT) associated virus development resources to its own maturation. The presented here mathematical model, attuned to the data from interplays between Zika WT viruses and their natural DVG in mammalian and mosquito cells, provides evidence that loss of uninfected cells is attenuated by the DVG development processes. This model enabled us to estimate rates of the virus development processes in the WT/DVG interplay, determine the key processes, and show that the key processes are faster in mosquito cells than in mammalian ones. In general, the presented model and its detailed study suggest in what important virus development processes the therapeutically efficient DVG might compete with WT: this may help in assembling engineered DVGs for ZIKV and other flaviviruses.