Novel Plant-Derived Recombinant Human Interferons with Broad Spectrum Antiviral Activity
ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD VIROLOGY DIV
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Type I interferons IFNs are potent mediators of the innate immune response to viral infection. IFNs released from infected cells bind to a receptor IFNAR on neighboring cells, triggering signaling cascades that limit further infection. Subtle variations in amino acids can alter IFNAR binding and signaling outcomes. We used a new gene crossbreeding method to generate hybrid, type I human IFNs with enhanced antiviral activity against four dissimilar, highly pathogenic viruses. Approximately 1400 novel IFN genes were expressed in plants, and the resultant IFN proteins were screened for antiviral activity. Comparing the gene sequences of a final set of 12 potent IFNs to those of parent genes revealed strong selection pressures at numerous amino acids. Using three-dimensional models based on a recently solved experimental structure of IFN bound to IFNAR, we show that many but not all of the amino acids that were highly selected for are predicted to improve receptor binding.