ArticlePLoS biology2019
Combinatorial mutagenesis of rapidly evolving residues yields super-restrictor antiviral proteins.
Article in PLoS biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 21 citations in OpenAlex.
- The potential impacts of human genetics on virus emergence.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Heterozygous and generalist MxA super-restrictors overcome breadth-specificity trade-offs in antiviral restriction.Science advances · 2025Article
- Article
- Systematic genetic characterization of the human PKR kinase domain highlights its functional malleability to escape a poxvirus substrate mimic.bioRxiv : the preprint server for biology · 2024Article
- Positive selection analyses identify a single WWE domain residue that shapes ZAP into a more potent restriction factor against alphaviruses.PLoS pathogens · 2024Article
- The Antiviral Activity of Equine Mx1 against Thogoto Virus Is Determined by the Molecular Structure of Its Viral Specificity Region.Journal of virology · 2023Article
- Conservation lost: host-pathogen battles drive diversification and expansion of gene families.The FEBS journal · 2021Review
- Highly-potent, synthetic APOBEC3s restrict HIV-1 through deamination-independent mechanisms.PLoS pathogens · 2021Article
- RTP4 Is a Potent IFN-Inducible Anti-flavivirus Effector Engaged in a Host-Virus Arms Race in Bats and Other Mammals.Cell host & microbe · 2020Article
- Tick-transmitted thogotovirus gains high virulence by a single MxA escape mutation in the viral nucleoprotein.PLoS pathogens · 2020Article
- Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races.eLife · 2020Article
- Mx genes: host determinants controlling influenza virus infection and trans-species transmission.Human genetics · 2020Review
- A Rapidly Evolving Polybasic Motif Modulates Bacterial Detection by Guanylate Binding Proteins.mBio · 2020Article
- Article
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
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 approximately 700 variants of human MxA, generated by combinatorial mutagenesis, for their ability to restrict Thogotovirus (THOV). We identified MxA super-restrictors with increased binding to the THOV nucleoprotein (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 trade-offs that could otherwise constrain their adaptive landscape.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.