The sociality continuum of viruses: a commentary on Leeks et al. 2023

Viruses are undoubtedly the most abundant and diverse biological entities on Earth (Koonin et al., 2023), displaying a wide variation in genome composition and structure, hosts they infect or replication dynamics. Studying their evolution is essential to understanding and managing their impact on human and animal health, as well as on our ecosystems, but they can also shed light on the evolution of life on Earth. Viruses indeed represent the closest contemporary forms of the pre-cellular world, at the border of ‘life’ (Koonin & Starokadomskyy, 2016), with some virus groups probably tracing their polyphyletic origins before the last universal cellular ancestor (Krupovic et al., 2019). Viruses are, like other microbes, also convenient models to study evolution (Elena & Sanjuán, 2007). They present several advantages for conducting experimental evolution studies: short generation time, large population size and relative simplicity of experimental settings (McDonald, 2019). In addition, viruses, especially RNA viruses, are characterized by high mutation rates, several orders of magnitude higher than the mutation rate of their hosts due to poor replication fidelity (Duffy, 2018; Sanjuán et al., 2010). This makes ‘long-term’ evolutionary experiments, including multiple replicates and varying conditions, possible within the timeframe of research projects. General evolutionary biology concepts have been experimentally explored using viruses, such as Muller's ratchet, the Red Queen hypothesis or convergent evolution (for review, see Moya et al., 2004). In their review in this issue of Journal of Evolutionary Biology, (Leeks et al., 2023) argue that social interactions count among the evolutionary topics that can be explored using viruses. Discussions between general evolutionary biologists and evolutionary virology are sometimes difficult, due to evolutionary virology's own terminology in 40 years of semi-independent developments (Geoghegan & Holmes, 2018). However, the challenges do not only come from field-specific semantics but also more profound differences in viruses' biology compared to other organisms. One of the most pressing open challenges, to my opinion, but also the most discussed, relates to the third and fifth open questions outlined by (Leeks et al., 2023) in their review: what is the viral ‘individual’? It is, indeed, a fundamental definition to characterize social interactions, that is, interactions between individuals. Viruses, especially RNA viruses, always exist in some form of social interaction, which is indissociable from their core biology. Indeed, RNA viruses occur within infected cells as a population of slightly different but related genotypes, a ‘mutant spectrum’. This is due to the mutation rate of RNA viruses, estimated to lead to a mutation at every genome copy during replication (Lauring & Andino, 2010). If we consider single genomes as individuals, as Leeks et al. suggest, social interactions will thus start at this level, after just a few rounds of replication. To support such a definition, there is ample evidence for various dynamics of interactions at this scale, such as cheating or cooperative behaviours (e.g. reviewed in Leeks et al., 2023 or Domingo & Perales, 2019). This population can manifest some surprising evolutionary characteristics that led some authors to consider the whole mutant spectrum as the unit of selection rather than individual genomes within the population. This idea derives from the ‘quasispecies theory’ (Domingo & Perales, 2019), which can be seen, despite a different conceptual history, as an adaptation of population genetics for highly mutational asexual haploid organisms (Wilke, 2005). One of these characteristics, for example, is that under a high mutation rate and in a rugged fitness landscape, interactions within the population can increase the average population fitness rather than the selection of high-fitness value genotypes. This dynamic was termed ‘survival of the flattest’ in contrast to the classical Darwinian ‘survival of the fittest’ (Wilke et al., 2001), a form of increased mutational robustness (Geoghegan & Holmes, 2018). In this case, quasispecies theory does fundamentally agree with group selection models (Holmes & Moya, 2002), which has been shown experimentally for an RNA virus (Bordería et al., 2015). While the reality of specific prediction of quasispecies theory for viruses in nature is still debated (Geoghegan & Holmes, 2018), the potential importance of group selection, especially for RNA viruses, cannot be neglected. Defining viral genomes as individuals thus leads to a fundamental decoupling between ‘individual’ and ‘unit of selection’. Alternatively, one could consider the mutant spectrum (i.e. the isolate, the strain, the mutant spectrum) as the viral ‘individual’, thus coupling ‘individual’ and ‘unit of selection’ again. This would be, however, in direct contradiction with the classical definition of an individual, as stated by (Leeks et al., 2023) ‘the largest unit at which we expect minimal evolutionary conflict between distinct entities’. Co-infections of different strains of the same virus (i.e. multiple mutant spectrums) appear to be relatively common and allow for genetic exchanges between viral genomes only distantly related (Pérez-Losada et al., 2015), as well as other forms of interactions, including competition or cooperation (e.g. reviewed in (Leeks et al., 2023) or Sanjuán, 2021). In these cases, can we talk about co-infection leading to potential social interactions (i.e. does social interactions occur on the population level) or do we see the early stages of forming a new mutant spectrum (i.e. social interactions at the genome level)? In any case, and irrespective of the definition of the viral ‘individual’ or ‘unit of selection’, it is evident that exploring the interaction between two different viral isolates means looking at the nested interaction of two mutant spectrums, themselves characterized by internal interactions between single genomes. This distinction is hardly ever made clear, however. Studies and reviews of viral social interactions do not really distinguish between these two nested layers, and indiscriminately switch between them, which is potentially confusing. On a final note, all organisms on Earth can host several viruses (Koonin et al., 2023), most of the time probably simultaneously (Du et al., 2022). Such co-infections with more distantly related viruses allow for interspecific interaction, leading to complex community ecology dynamics when considering all the possible interactions between viruses within a single host. One could even consider the interaction between the virus and the host, which does not always lead to conflicts but sometimes cooperation (Roossinck & Bazán, 2015; Villarreal, 2009). I would however be cautious in not over-extending the reach of sociovirology beyond the domain of social (i.e. between individuals) interactions: interactions between viruses of different taxonomic ranks or with their hosts are not social but ecological. It is thus clear that viruses exist under a continuum of interactions, ranging from social (kin-like, intra-specific) to ecological (interspecific, community ecology) interactions (Figure 1). Defining where the ‘individual’ ends and where the ‘social’ starts can thus be more challenging than for other organisms. Similarly, defining where the ‘social’ ends and the ‘ecological’ starts can also be challenging when the borders between species might not always be clear (Bobay & Ochman, 2018). The nested nature of the interactions, from the single genome to the whole meta-population and ecological interactions, might lead to complex experimental outcomes that may contradict each other between studies. To address this challenge, I would call for an explicit description of the level of interaction studied, either experimentally, in models or reviews, to avoid confusion and allow proper comparison and understanding between studies. Stating the study of ‘co-infections’ or ‘virus-virus’ interactions, for example, is insubstantial, as viruses always experience co-infections and virus-virus interactions. Does the study deal with dynamics within the mutant spectrum? Or between different mutant spectrums? I believe a proper description of the level of interaction studied is necessary for each study through the shared use of common concepts and vocabularies between experimentalists and theoreticians from virology or evolutionary biology. This recommendation will hopefully allow the nascent field of sociovirology to move along the most straightforward path possible. As the field develops, it is time to set good practices: let us do our best so that evolutionary biologists and virologists studying viruses can also cooperate while keeping in mind the quirks of the viral world. The ‘life’ of viruses is definitively a highly social one, and deciphering it will undoubtedly hold fascinating insights for virology, evolutionary biology and all related fields. Sebastian Lequime: Conceptualization; writing—original draft; writing—review & editing; visualization. I thank Nadja Brait, dr. Marjon de Vos and dr. Thomas Hackl for fruitful discussions on interactions. The author declares no conflicts of interest. No data are associated with this article.