Abstract
Cellular coinfection between multiple virions is a common feature of viral infections. The collective virus-virus interactions enabled by these coinfections can influence the fitness of viral populations and give rise to novel infection phenotypes. Multi-strain coinfections allow viral resources to be shared between multiple individuals, and enable genetic combination and recombination between genotypes, potentially giving rise to hybrid progeny with enhanced fitness. However, coinfection can also impose fitness costs in certain situations. For example, resource sharing among viruses can lead to the persistence of low-fitness genotypes, and reassortment between different strains can lead to negative inter-segment epistasis when genes are poorly matched to one another. Thus, the fitness implications of cellular coinfection are poorly defined and likely context dependent. To investigate the specific conditions that lead to positive or negative fitness consequences for multi-strain coinfections, we formulated a model in which different genotypes of a three-segment virus replicate under varying degrees of inter-strain mixing. We observed that increased mixing had negative fitness consequences under a variety of scenarios, and that this effect was exacerbated with increasing genetic divergence between strains. Inter-strain mixing only enhanced viral fitness (a) when positive genetic dominance interactions were at play, and (b) under very specific conditions of selective pressure. We also observed that reassortment arising from mixing could generate hybrid genotypes with higher fitness than either parental virus, but that these outcomes were relatively rare. Overall, using a model segmented virus, we found that the heterologous coinfection was deleterious under most conditions, suggesting that it may be beneficial for many viruses to limit the extent of cellular coinfection.