Summary of article Combinatorial mutagenesis of rapidly evolving residues yields super-restrictor antiviral proteins. Rossana Colón-Thillet, Emily Hsieh, Laura Graf, Richard N McLaughlin Jr, Janet M Young, Georg Kochs, Michael Emerman, Harmit S Malik PLoS Biol. 2019 Oct 1;17(10):e3000181. doi: 10.1371/journal.pbio.3000181. eCollection 2019 Oct PMID: 31574080 PMCID: PMC6772013 DOI: 10.1371/journal.pbio.3000181 https://pubmed.ncbi.nlm.nih.gov/31574080/

Host-virus interactions are antagonistic: one species (the virus) benefits and the other (the host) is harmed. Viruses interact with the host cells by binding to the surface of the host proteins.

One way to stop such virus-host interactions is for the host to change (mutate) the structure of the surface of the protein to which the virus binds, with the intent to disrupt such interaction. One way for the virus to fight back is by adapting to the new protein structure of the host. For that, the virus makes changes (mutations) in the structure of its proteins. 

This back-and-forth process of recurrent protein modification between the host and the virus is called “positive selection.” Usually, this “positive selection” occurs only on a small area of the protein, to maximize the disruption of the binding between the virus and its hots. The amount of disruption dictates the strength of the viral infection.

Combinatorial mutagenesis is a bioengineering technique where multiple mutants (variations) of a protein are simultaneously engineered; then the effects on the function of each mutant protein are evaluated.

This study focused on understanding how the “positive selection” proteins involved in the interaction virus-host can be modified to restrict such interaction. For that, the researchers created several versions of the human protein “MxA”,  the main protein involved in the virus-human interaction, and which intervenes in human immunity against a broad spectrum of viruses. The researchers made various mutations on MxA to assess how that affected its functions. The mutated proteins were tested against the virus THOV, which is frequently used for research.

The researchers found several mutant proteins that disrupt the interaction between the host and the virus THOV very efficiently.

These results demonstrated that it is possible to use combinatorial mutagenesis to engineer antiviral proteins that restrict the interactions between a virus and its host.

These results are promising for advancing antiviral therapies, which will be critical to avoid a new pandemic.