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
Xy. Deng et al., 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, BLOOD, 94(4), 1999, pp. 1165-1173
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.