Blockade of chemokine activity by a soluble chemokine binding protein from vaccinia virus.
Chemokines direct migration of immune cells into sites of inflammation and infection. Chemokine receptors are seven-transmembrane domain proteins that, in contrast to other cytokine receptors, cannot be easily engineered as soluble chemokine inhibitors. Poxviruses encode several soluble cytokine receptors to evade immune surveillance, providing new strategies for immune modulation. Here we show that vaccinia virus and other orthopoxviruses (cowpox and camelpox) express a secreted 35-kDa chemokine binding protein (vCKBP) with no sequence similarity to known cellular chemokine receptors. The vCKBP binds CC, but not CXC or C, chemokines with high affinity (Kd = 0.1-15 nM for different CC chemokines), blocks the interaction of chemokines with cellular receptors, and inhibits chemokine-induced elevation of intracellular calcium levels and cell migration in vitro, thus representing a soluble inhibitor that binds and sequesters chemokines. The potential of vCKBP as a therapeutic agent in vivo was illustrated in a guinea pig skin model by the blockade of eotaxin-induced eosinophil infiltration. a feature of allergic inflammatory reactions. Furthermore, vCKBP may enable the rational design of antagonists to neutralize pathogens that use chemokine receptors to initiate infection, such as HIV or the malarial parasite.
Alcamí
A
A
Sir William Dunn School of Pathology, University of Oxford, United Kingdom.
Symons
J A
JA
Collins
P D
PD
Williams
T J
TJ
Smith
G L
GL
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054413:Chemokine CCL11; D018925:Chemokines / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000378:metabolism; D002631:Chemotactic Factors, Eosinophil / Q000037:antagonists & inhibitors; D015608:Cowpox virus / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006801:Humans; D008970:Molecular Weight; D018155:Orthopoxvirus / Q000235:genetics / Q000276:immunology; D011509:Proteoglycans / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D012884:Skin Window Technique; D012995:Solubility; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C515456:CCL11 protein, human; D002352:Carrier Proteins; D054413:Chemokine CCL11; D018925:Chemokines; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D016207:Cytokines; D011509:Proteoglycans; D019707:Receptors, Chemokine; D014764:Viral Proteins