THE PURIFIED MYXOMA VIRUS GAMMA-INTERFERON RECEPTOR HOMOLOG M-T7 INTERACTS WITH THE HEPARIN-BINDING DOMAINS OF CHEMOKINES

The myxoma virus T7 protein M-T7 is a functional soluble gamma interfe ron receptor homolog that has previously been shown to bind gamma inte rferon and inhibit its antiviral activities in a species-specific mann er, but gene knockout analysis has suggested a further role for M-T7 i n blocking leukocyte influx into infected lesions, We purified M-T7 to apparent homogeneity and showed that M-T7 is an N-linked glycoprotein that appears to be a stable homotrimer with a molecular mass of appro ximately 113 kDa in solution. M-T7, in addition to forming inhibitory complexes with rabbit gamma interferon, was also shown to bind to huma n interleukin-8, a prototypic member of the chemokine superfamily, Mor eover, M-T7 was able to interact promiscuously with all members of the CXC, CC, and C chemokine subfamilies tested. Binding of human RANTES to M-T7 can be competed by rabbit gamma interferon and also by cold RA NTES competitor with a 50% inhibitory concentration of 900 nM, Althoug h M-T7 retains binding to a number of interleukin-8 N-terminal (ELR) d eletion mutants, binding to mutants containing deletions in the C-term inal heparin-binding domain of interleukin-8 is abrogated, Furthermore , heparin effectively competes the interaction of M-T7 with the chemok ine RANTES hut not with rabbit gamma interferon, We propose that this novel M-T7 interaction with members of the chemokine superfamily may b e facilitated through the conserved heparin-binding domains found in a wide spectrum of chemokines and that M-T7 may function by modulating chemokine-glycosaminoglycan interactions in virus-infected tissues.