The HIV-1 cell entry inhibitor T-20 potently chemoattracts neutrophils by specifically activating the N-formylpeptide receptor

T-20, a synthetic peptide corresponding to the heptad repeat sequence of HI V-1 gp41, blocks HIV-1 entry by targeting gp41, and is currently in clinica l trials as an anti-retroviral agent. We recently reported that in vitro T- 20 also functions as a phagocyte chemoattractant and; a chemotactic agonist at the phagocyte N-formylpeptide receptor (FPR). Here we show that T-20 is also a potent chemotactic agonist in vitro at a related human phagocyte re ceptor FPRL1R. To test the relative importance of FPR and FPRL1R in primacy cells, we identified the corresponding mouse T-20 receptors, mFPR and FPR2 , which are both expressed in neutrophils, and compared T-20 action on neut rophils from wild type and mFPR knockout mice. Surprisingly, although T-20 activates mFPR and FPR2 in transfected cells with equal potency and efficac y in both calcium flux and chemotaxis assays, neutrophils from mFPR knockou t mice did not respond to T-20. These results provide genetic evidence that FPR is the major phagocyte T-20 receptor in vivo and point to the potentia l feasibility of studying T-20 effects on immunity in a mouse model. This m ay help define the cause of local inflammation after T-20 injection that ha s recently been reported in Phase I clinical trials. (C) 2000 Academic Pres s.