T21/DP107, a synthetic leucine zipper-like domain of the HIV-1 envelope gp41, attracts and activates human phagocytes by using G-protein-coupled formyl peptide receptors

A leucine zipper-like domain, T21/DP107, located in the amino terminus of t he ectodomain of gp41, is crucial to the formation of fusogenic configurati on of the HIV-1 envelope protein gp41. We report that the synthetic T21/DP1 07 segment is a potent stimulant of migration and calcium mobilization in h uman monocytes and neutrophils, The activity of T21/DP107 on phagocytes was pertussis toxin-sensitive, suggesting this peptide uses Gi-coupled seven-t ransmembrane receptor(s), Since the bacterial chemotactic peptide fMLP part ially desensitized the calcium-mobilizing activity of T21/DP107 in phagocyt es, we postulated that T21/DP107 might preferentially use a lower affinity fMLP receptor. By using cells transfected to express cloned prototype chemo tactic N-formyl peptide receptor (FPR) or its variant, FPR-like 1 (FPRL1), we demonstrate that T21/DP107 activates both receptors but has a much highe r efficacy for FPRL1, In addition, T21/DP107 at nM concentrations induced m igration of FPRL1-transfected human embryonic kidney 293 cells. In contrast , fMLP did not induce significant chemotaxis of the same cells at a concent ration as high as 50 mu M Although a lipid metabolite, lipoxin A4, was a hi gh-affinity ligand for FPRL1, it was not reported to induce Ca2+ mobilizati on or chemotaxis in FPRL1-transfected cells. Therefore, T21/DP107 is a firs t chemotactic peptide agonist identified thus far for FPRL1. Our results su ggest that this peptide domain of the HIV-1 gp41 may have the potential to activate host innate immune response by interacting with FPR and FPRL1 on p hagocytes.