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Collective Infectious Units and the Social Evolution of Viruses

Periodic Reporting for period 4 - Vis-a-Vis (Collective Infectious Units and the Social Evolution of Viruses)

Reporting period: 2021-11-01 to 2022-04-30

In contrast to the classical notion that virions function as independent infectious units, recent work has shown that viruses are often transmitted as more complex structures, such as aggregates of virions or lipid vesicles harboring multiple infectious particles ("collective infectious units"). These recent discoveries lay the groundwork for the evolution of social interactions, a previously unappreciated facet of viruses. This project has investigated how collective infectious units drive virus-virus interactions. To do so, we have used the conceptual framework provided by the theory of social evolution, which had previously been validated in different types or organisms, but not in viruses. Our model systems have included enteroviruses, vesicular stomatitis viruses, baculoviruses and bacteriophages. Experimental work with these viruses has been complemented by simulations and modeling. We have shown that collective spread can provide viruses with an immediate fitness benefit that is most relevant during the early stages of infection. These benefits stem from faster production of viral progeny, which can help viruses stay ahead of innate immune responses. However, in the long term, collective spread may favor the emergence of defective viruses that function as social cheaters and have a negative impact on viral fitness. The emergence of cheaters depends on a number of factors, such as the genetic composition of collective infectious units, the spatial structure of the population, and the frequency with which collective infectious units are formed. The results of this project have been published in 16 original research articles and eight reviews, opinion articles or book chapters. The results have also been presented in multiple invited talks and congresses, as well as in journals, blogs and interviews aimed at the general public.
The main objectives of the project have been successfully achieved. We have characterized different types of collective infectious units (CIUs), such as virion aggregates and virion-containing lipid microvesicles, and investigated the genetic basis of these CIUs. We have shown that CIUs promote cellular co-infection with multiple viral particles. Co-infection enhances short-term viral fitness by accelerating early progeny production, which allows viruses to outpace innate immunity. We have found that viral replication is an inherently cooperative process, such that cells initially infected by multiple viral particles produce a disproportionately greater amount of viral progeny. Although cooperation between different virus variants is probably not responsible for the fitness advantage associated with CIUs, by promoting genetic complementation CIUs could increase within-host viral diversity and viral evolvability. We have shown that CIUs can promote the emergence of defective viruses, which function as social cheats. Some viruses, such as enteroviruses and baculoviruses, exhibit mechanisms to increase genetic relatedness within CIUs, thereby preventing the spread of cheaters. We have also shown that virus-virus interactions can take place in the absence of cellular co-infection, such as during evasion of innate immunity mediated by paracrine signaling. Finally, we have extended the project objectives to bacteriophages by investigating a recently discovered phage communication system and exploring the role of phage depolymerases as a public good involved in host tropism.
We have shown for the first time that viral innate immunity evasion is a social trait that can be modeled using well-established theoretical frameworks, such as Hamilton's rule and game theory. This brings together concepts from the fields of social evolution and virology and should inspire further work in this direction.

We have demonstrated and characterized the process by which collective infectious units arise from free virions in a model virus (vesicular stomatitis virus), and found that this process is triggered by saliva, a natural dissemination pathway for this and other viruses.

We have unraveled the genetic basis of viral encapsulation in lipid microvesicles in an enterovirus, which should stimulate research on the association between viral replication and cellular membranes.

We have also demonstrated the Allee effect in a virus. This effect consists of a positive relationship between the number of viral genomes that initiate infection and the per-capita reproduction rate of the virus. The Allee effect is a well-known concept in ecology, but it has never been applied to viruses.

We have shown that viral replication is an inherently cooperative process, a finding of great generality and with long-term implications in virology.
Vesicular stomatitis virion aggregate