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Combinatorial mutagenesis of rapidly-evolving residues yields super-restrictor antiviral proteins

By Rossana Colón-Thillet, Emily Hsieh, Laura Graf, Richard N. McLaughlin, Janet M. Young, Georg Kochs, Michael Emerman, Harmit S. Malik

Posted 22 Feb 2019
bioRxiv DOI: 10.1101/557264 (published DOI: 10.1371/journal.pbio.3000181)

Antagonistic interactions drive host-virus evolutionary arms-races, which often manifest as recurrent amino acid changes ( i.e ., positive selection) at their protein-protein interaction interfaces. Here, we investigated whether combinatorial mutagenesis of positions under positive selection in a host antiviral protein could enhance its restrictive properties. We tested ~700 variants of human MxA, generated by combinatorial mutagenesis, for their ability to restrict Thogoto orthomyxovirus (THOV). We identified MxA super-restrictors with increased binding to THOV NP target protein and 10-fold higher anti-THOV restriction relative to wild-type human MxA, the most potent naturally-occurring anti-THOV restrictor identified. Our findings reveal a means to elicit super-restrictor antiviral proteins by leveraging signatures of positive selection. Although some MxA super-restrictors of THOV were impaired in their restriction of H5N1 influenza A virus (IAV), other super-restrictor variants increased THOV restriction without impairment of IAV restriction. Thus, broadly acting antiviral proteins such as MxA mitigate breadth-versus-specificity tradeoffs that could otherwise constrain their adaptive landscape.

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