N36, a synthetic N-terminal heptad repeat domain of the HIV-1 envelope protein gp41, is an activator of human phagocytes

Human immunodeficiency virus type 1 (HIV-1) envelope protein gp41 mediates viral fusion with human host cells. In this study we show that N36, a synth etic peptide derived from the N-terminus of gp41, induced directional migra tion and calcium mobilization in human monocytes and neutrophils, The activ ity of N36 on phagocytes was pertussis toxin sensitive, suggesting involvem ent of a Gi-coupled seven-transmembrane receptor(s), Since high concentrati ons of the bacterial chemotactic peptide fMet-Leu-Phe (fMLF) partially dese nsitized the calcium mobilizing activity of N36 in phagocytes, we postulate d that N36 might use a low-affinity fMLF receptor. By using cells stably ex pressing fMLF receptor FPR or FPRL1, we demonstrate that N36 uses FPRL1 as a functional receptor. Our results suggest that HIV-1 gp41 may contain a fr agment(s) that activates the innate host immune cells through FPRL1, Since the activation of FPRL1 in monocytes has been shown to heterologously desen sitize chemokine receptors, the reduced phagocyte response to chemoattracta nts seen in AIDS patients may be attributed, at least in part, to heterolog ous desensitization. (C) 2000 Academic Press.