Identification of a gammaherpesvirus selective chemokine binding protein that inhibits chemokine action

Chemokines are involved in recruitment and activation of hematopoietic cell s at sites of infection and inflammation. The M3 gene of gamma HV68, a gamm a-2 herpesvirus that infects and establishes a lifelong latent infection an d chronic vasculitis in mice, encodes an abundant secreted protein during p roductive infection. The M3 gene is located in a region of the genome that is transcribed during latency. We report here that the M3 protein is a high affinity broad-spectrum chemokine scavenger, The M3 protein bound the CC c hemokines human regulated upon activation of normal T-cell expressed and se creted (RANTES), murine macrophage inflammatory protein 1 alpha (MIP-1 alph a), and murine monocyte chemoattractant protein 1 (MCP-1), as well as the h uman CXC chemokine interleukin-8, the murine C chemokine lymphotactin, and the murine CX3C chemokine fractalkine with high affinity (K-d = 1.6 to 18.7 nM). M3 protein chemokine binding was selective, since the protein did not bind seven other CXC chemokines (K-d > 1 mu M). Furthermore, the M3 protei n abolished calcium signaling in response to murine MIP-La and murine MCP-1 and not to murine KC or human stromal cell-derived factor 1 (SDF-1), consi stent with the binding data. The M3 protein was also capable of blocking th e function of human CC and CXC chemokines, indicating the potential for the rapeutic applications, Since the M3 protein lacks homology to known chemoki nes, chemokine receptors, or chemokine binding proteins, these studies sugg est a novel herpesvirus mechanism of immune evasion.