Novel plant-derived recombinant human interferons with broad spectrum antiviral activity.
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.
U.S. Army Medical Research Institute of Infectious Diseases, Virology Division, Fort Detrick, MD 21702, USA.
Jeffrey W
JW
Koehler
Lesley C
LC
Dupuy
Aura R
AR
Garrison
Brett F
BF
Beitzel
Michelle J
MJ
Richards
Daniel R
DR
Ripoll
Anders
A
Wallqvist
Shia-Yen
SY
Teh
Andrew A
AA
Vaewhongs
Fakhrieh S
FS
Vojdani
Hal S
HS
Padgett
Connie S
CS
Schmaljohn
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D006801:Humans; D007370:Interferon Type I / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D016415:Sequence Alignment; D014026:Nicotiana / Q000235:genetics; D014709:Vero Cells; D014780:Viruses / Q000187:drug effects*
D000998:Antiviral Agents; D007370:Interferon Type I; D011994:Recombinant Proteins