Constrained evolvability of interferon suppression in an RNA virus

• Published in: Scientific reports Vol. 6; no. 1; p. 24722
• Main Authors: Garijo, Raquel, Cuevas, José M., Briz, Álvaro, Sanjuán, Rafael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.04.2016; Nature Publishing Group
• Subjects: 13/106; 45/70; 49/109; 631/181/2475; 631/326/596/2554; Adaptation, Biological; Biological Evolution; Cell Line; Genetic Variation; Genomes; Humanities and Social Sciences; Humans; Immunity, Innate; Innate immunity; Interferon; Interferons - metabolism; Matrix protein; Models, Biological; multidisciplinary; Mutation; Oncolysis; Phosphorylation; Reproductive fitness; RNA Virus Infections - etiology; RNA Virus Infections - metabolism; RNA viruses; RNA Viruses - physiology; Science; Science (multidisciplinary); Stomatitis; Viral infections; Viral Proteins - genetics; Viral Proteins - metabolism; Virus Replication; Viruses
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep24722

Innate immunity responses controlled by interferon (IFN) are believed to constitute a major selective pressure shaping viral evolution. Viruses encode a variety of IFN suppressors, but these are often multifunctional proteins that also play essential roles in other steps of the viral infection cycle, possibly limiting their evolvability. Here, we experimentally evolved a vesicular stomatitis virus (VSV) mutant carrying a defect in the matrix protein (M∆51) that abolishes IFN suppression and that has been previously used in the context of oncolytic virotherapy. Serial transfers of this virus in normal, IFN-secreting cells led to a modest recovery of IFN blocking capacity and to weak increases in viral fitness. Full-genome ultra-deep sequencing and phenotypic analysis of population variants revealed that the anti-IFN function of the matrix protein was not restored, and that the Mdelta51 defect was instead compensated by changes in the viral phosphoprotein. We also show that adaptation to IFN-secreting cells can be driven by the selection of fast-growing viruses with no IFN suppression capacity, and that these population variants can be trans-complemented by other, IFN-suppressing variants. Our results thus suggest that virus-virus interactions and alternative strategies of innate immunity evasion can determine the evolution of IFN suppression in a virus.