Peptide T blocks GP120/CCR5 chemokine receptor-mediated chemotaxis

We previously reported that certain short gp120 V2 region peptides homologo us to vasaoactive intestinal peptide (VIP), such as "peptide T," were poten t inhibitors of gp120 binding, infectivity, and neurotoxicity. The present study shows that synthetic V2-region-derived peptides have potent intrinsic chemotaxis agonist activity for human monocytes and also act as antagonist s of high-affinity (0.1 pM) gp120-mediated monocyte chemotaxis. Selectivity is shown in that peptide T is more potent at suppressing M-tropic than T-t ropic gp120 chemotaxis. Peptide T was also able to suppress monocyte chemot axis to MIP-1 beta, a chemokine with selectivity for CCR5 chemokine recepto rs, while chemotaxis of the more promiscuous ligand RANTES was not inhibite d, nor was chemotaxis mediated by SDF-1 alpha. In order to determine if pep tide T mediated its gp120 antagonistic effects via modulation of CCR5 recep tors, RANTES chemotaxis was studied using a CCR5 receptor-transfected HOS c ell line. In this case, RANTES chemotaxis was potently inhibited by V2-regi on-derived short peptides. Peptide T also partially suppressed I-125-MIP1-b eta binding to human monocytes, suggesting action at a subset of MIP1-beta receptors. The V2 region of gp120 thus contains a potent receptor binding d omain and synthetic peptides derived from this region modulate CCR5 chemoki ne receptor chemotactic signaling caused by either gp120 or chemokine ligan ds. The results have therapeutic implications and may explain recent clinic al improvements, in that HIV/gp120 actions at CCR5 receptors, such as occur in the brain or early infection, would be susceptible to peptide T inhibit ion. (C) 1999 Academic Press.