Abstract
Host antiviral proteins engage in evolutionary arms races with viruses, in which both sides rapidly evolve at interaction interfaces to gain or evade immune defense. For example, primate TRIM5α uses its rapidly evolving 'v1' loop to bind retroviral capsids, and single mutations in this loop can dramatically improve retroviral restriction. However, it is unknown whether such gains of viral restriction are rare, or if they incur loss of pre-existing function against other viruses. Using deep mutational scanning, we comprehensively measured how single mutations in the TRIM5α v1 loop affect restriction of divergent retroviruses. Unexpectedly, we found that the majority of mutations increase weak antiviral function. Moreover, most random mutations do not disrupt potent viral restriction, even when it is newly acquired via a single adaptive substitution. Our results indicate that TRIM5α's adaptive landscape is remarkably broad and mutationally resilient, maximizing its chances of success in evolutionary arms races with retroviruses.
Highlights
Mammalian genomes combat the persistent threat of viruses by encoding a battery of cellintrinsic antiviral proteins, termed restriction factors, that recognize and inhibit viral replication within host cells
We found that, rather than the evolutionary landscape of TRIM5α being narrowly constrained among all possible amino acid substitutions, the majority of random mutations in the v1 loop resulted in gains of antiviral restriction
Single amino acid changes at residue 332 are responsible for dramatic differences in antiviral restriction
Summary
Mammalian genomes combat the persistent threat of viruses by encoding a battery of cellintrinsic antiviral proteins, termed restriction factors, that recognize and inhibit viral replication within host cells. The potency of restriction factors places selective pressure on viruses to evade recognition in order to complete replication (Duggal & Emerman, 2012). Viral escape spurs adaptation of restriction factors, by selecting for variants that re-establish viral recognition and thereby restriction (McCarthy, Kirmaier, Autissier, & Johnson, 2015). Mutual antagonism between viruses and their hosts drives cycles of recurrent adaptation, in prey-predator-like genetic arms races (Van Valen, 1973). These arms races result in the rapid evolution of restriction factors, which accumulate amino acid mutations at their virus-binding interface at a higher than expected rate D. Daugherty & Malik, 2012)
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