PT  - JOURNAL ARTICLE
AU  - Rossana Colón-Thillet
AU  - Emily Hsieh
AU  - Laura Graf
AU  - Richard N McLaughlin, Jr
AU  - Georg Kochs
AU  - Michael Emerman
AU  - Harmit S. Malik
TI  - Evolution-guided design of super-restrictor antiviral proteins reveals a breadth-versus-specificity tradeoff
AID  - 10.1101/557264
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 557264
4099  - http://biorxiv.org/content/early/2019/02/22/557264.short
4100  - http://biorxiv.org/content/early/2019/02/22/557264.full
AB  - Host-virus evolutionary arms-races are driven by antagonistic interactions and 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 ∼ 800 variants of the human MxA protein, 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. However, MxA super-restrictors of THOV were impaired in their restriction of influenza A virus. Our findings thus reveal a breadth-versus-specificity tradeoff that constrains the adaptive landscape of antiviral proteins.