A synthetic peptide derived from human immunodeficiency virus type 1 gp120downregulates the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes by activating the 7-transmembrane G-protein-coupled receptor FPRL1/LXA4R

Because envelope gp120 of various strains of human immunodeficiency virus t ype 1 (HIV-1) downregulates the expression and function of a variety of che moattractant receptors through a process of heterologous desensitization, w e investigated whether epitopes derived from gp120 could mimic the effect. A synthetic peptide domain, designated F peptide, corresponding to amino ac id residues 414-434 in the V4-C4 region of gp120 of the HIV-1 Bru strain, p otently reduced monocyte binding and chemotaxis response to macrophage infl ammatory protein 1 beta (MIP-1 beta) and stromal cell-derived factor 1 alph a (SDF-1 alpha), chemokines that use the receptors CCR5 and CXCR4, respecti vely. Further study showed that F peptide by itself is an inducer of chemot axis and calcium mobilization in human monocytes and neutrophils. In cross- desensitization experiments, among the numerous chemoattractants tested, on ly the bacterial chemotactic peptide fMLF, when used at high concentrations , partially attenuated calcium mobilization induced by F peptide in phagocy tes, suggesting that this peptide domain might share a 7-transmembrane, G-p rotein-coupled receptor with fMLF By using cells transfected with cDNAs enc oding receptors that interact with fMLF, we found that F peptide uses an fM LF receptor variant, FPRL1, as a functional receptor. The activation of mon ocytes by F peptide resulted in downregulation of the cell surface expressi on of CCR5 and CXCR4 in a protein kinase C-dependent manner. These results demonstrate that activation of FPRL1 on human moncytes by a peptide domain derived from HIV-1 gp120 could lead to desensitization of cell response to other chemoattractants. This may explain, at least in part, the initial act ivation of innate immune responses in HIV-1-infected patients followed by i mmune suppression.