Beneficial coinfection can promote within-host viral diversity

Abstract

In many viral infections, a large number of different genetic variants can coexist within a host, leading to more virulent infections that are better able to evolve antiviral resistance and adapt to new hosts. But how is this diversity maintained? Why do faster-growing variants not outcompete slower-growing variants, and erode this diversity? One hypothesis is if there are mutually beneficial interactions between variants, with host cells infected by multiple different viral genomes producing more, or more effective, virions. We modelled this hypothesis with both mathematical models and simulations, and found that moderate levels of beneficial coinfection can maintain high levels of coexistence, even when coinfection is relatively rare, and when there are significant fitness differences between competing variants. Rare variants are more likely to be coinfecting with a different variant, and hence beneficial coinfection increases the relative fitness of rare variants through negative frequency dependence, and maintains diversity. We further find that coexisting variants sometimes reach unequal frequencies, depending on the extent to which different variants benefit from coinfection, and the ratio of variants which leads to the most productive infected cells. These factors could help drive the evolution of defective interfering particles, and help to explain why the different segments of multipartite viruses persist at different equilibrium frequencies.

Multiple infection of cells changes the dynamics of basic viral evolutionary processes

“…As another example, it has been shown that mutually beneficial interactions among genetically different virus strains that lead to increased viral output from the infected cell can promote coexistence, even in the presence of significant fitness differences (Leeks et al. ). Such interactions will be incorporated into our modeling framework in future studies.…”

“…For example, it has been shown that frequent coinfection can have an overall deleterious effect on the virus population due to the persistence of defective or inferior virus strains, which outweighs the advantages derived from viral sex at high multiplicities (Froissart et al 2004). As another example, it has been shown that mutually beneficial interactions among genetically different virus strains that lead to increased viral output from the infected cell can promote coexistence, even in the presence of significant fitness differences (Leeks et al 2018). Such interactions will be incorporated into our modeling framework in future studies.…”

“…From a mathematical point of view, aspects of viral dynamics have been investigated in the context of multiple infection Perelson 2004, 2005;Wodarz and Levy 2011;Cummings et al 2012;Komarova et al 2012Komarova et al , 2013Asatryan et al 2015), including studies of competition dynamics and evolutionary processes Nowak and May 1994;van-Baalen and Sabelis 1995;Alizon and van Baalen 2008;Lipsitch et al 2009;Alizon et al 2013;Phan and Wodarz 2015;Leeks et al 2018), especially with a focus on recombination (Bretscher et al 2004;Althaus and Bonhoeffer 2005;Fraser 2005;Kouyos et al 2006;Vijay et al 2008). The effect of infection multiplicity on more basic evolutionary measures, such as the fixation probability of mutants, the time until mutant generation, and time until mutant invasion or fixation, has, however, so far not been investigated in detail.…”

“…; Phan and Wodarz ; Leeks et al. ), especially with a focus on recombination (Bretscher et al. ; Althaus and Bonhoeffer ; Fraser ; Kouyos et al.…”

The evolution of collective infectious units in viruses

“…By allowing the same host cell to be infected by multiple viral genomes simultaneously, CIUs allow for interactions between viruses even when we would otherwise expect coinfection to be rare, such as when there are strong population bottlenecks or low ratios of infectious viral particles to susceptible host cells (McCrone & Lauring 2018;Sanjuán 2018). Interactions between viral sequences can have important consequences for viral pathogenesis, diversity, and the evolution of antiviral resistance (Bordería et al 2015; Leeks et al 2018;Tanner et al 2014;Vignuzzi et al 2006; Xue et al 2016). Furthermore, CIUs allow for repeated interactions between viral sequences, and this sets the stage for viral social adaptations.…”