1887

Abstract

Gamma interferon (IFN-) production is important in the host response to, and recovery from, infection with (ECTV) and (VACV). The orthopoxviruses have evolved several mechanisms to subvert the IFN- response. IFN--binding protein (IFN-BP) is a virally encoded homologue of the host IFN- receptor that blocks the effects of IFN- in the infected host. Unlike the cellular receptors, whose ligand specificity is restricted to their own species, the orthopoxvirus IFN-BPs bind IFN- from several species. The reason for this relaxed specificity has yet to be explained. ECTV, a mouse pathogen, encodes an IFN-BP that has been shown to inhibit the activity of both human and murine IFN- (hIFN- and mIFN-, respectively). In contrast, the IFN-BP from VACV is unable to inhibit mIFN-, but retains activity against hIFN-. To determine which region(s) in the ECTV sequence is responsible for its ability to bind to mIFN- with high affinity, a series of chimeric IFN-BPs, as well as individual point mutants in the ECTV sequence corresponding to the amino acid changes from the VACV sequence, were constructed. The affinities of the chimeric and point mutant IFN-BPs for mIFN- were tested by using surface plasmon resonance and bioassay. By using this strategy, several key residues in the ligand-binding domains of the ECTV sequence have been identified that are responsible for high-affinity binding to mIFN-. Substitution of the ECTV residue at these positions in VACV resulted in a dramatic increase in the affinity of the VACV IFN-BP for mIFN-.

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2007-01-01
2021-08-03
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