The synthetic peptide WKYMVm attenuates the function of the chemokine receptors CCR5 and CXCR4 through activation of formyl peptide receptor-like 1

The G protein-coupled 7 transmembrane (STM) chemoattractant receptors can b e inactivated by heterologous desensitization. Earlier work showed that for mly peptide receptor-like 1 (FPRL1), an STM receptor with low affinity for the bacterial chemotactic, peptide formyl-methionyl-leucyl-phenylalamine (f MLF), is activated by peptide domains derived from the human immunodeficien cy virus (HIV)-1 envelope glycoprotein gp120 and its activation results in desensitization and downregulation of the chemokine receptors CCR5 and CXCR 4 from monocyte surfaces. This study Investigated the possibility of interf ering with the function of CCR5 or CXCR4 as HIV-1 coreceptors by activating FPRL1. Cell lines were established expressing FPRL1 in combination with CD 4/CXCR4 or CD4/CCR5 and the effect of a synthetic peptide, WKYMVm, a potent activator of formyl peptide receptors with preference for FPRL1 was determ ined. Both CXCR4 and CCR5 were desensitized by activation of the cells with WKYMVm via a staurosporine-sensitive pathway. This desensitization of CXCR 4 and CCR5 also attenuated their capacity as the fusion cofactors for HIV-1 envelope glycoprotein and resulted in a significant inhibition of p24 prod uction by cell lines infected with HIV-1 that use CCR5 or CXCR4 as corecept ors. Furthermore, WKYMVm inhibited the infection of human peripheral monocy te-derived macrophages and CD4(+) T lymphocytes by R5 or X4 strains of HIV- 1, respectively. These results indicate that heterologous desensitization o f CCR5 and CXCR4 by an FPRL1 agonist attenuates their major biologic functi ons and suggest an approach to the development of additional anti-HIV-1 age nts. (Blood. 2001;97:2941-2947) (C) 2001 by The American Society of Hematol ogy.