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Blood, 15 May 2001, Vol. 97, No. 10, pp. 2941-2947
CHEMOKINES
The synthetic peptide WKYMVm attenuates the function of the
chemokine receptors CCR5 and CXCR4 through activation of formyl
peptide receptor-like 1
Bao-Qun Li,
Michele A. Wetzel,
Judy A. Mikovits,
Earl E. Henderson,
Thomas J. Rogers,
Wanghua Gong,
Yingying Le,
Francis W. Ruscetti, and
Ji
Ming Wang
From the Intramural Research Support Program and the
Laboratory of Antiviral Drug Mechanism, NCI-Screening Technologies
Branch, SAIC Frederick, Laboratory of Molecular Immunoregulation, and
Laboratory of Leukocyte Biology, Division of Basic Science, National
Cancer Institute-Frederick Cancer Research Development Center,
Frederick, MD; and the Department of Microbiology and Immunology,
Temple University School of Medicine, Philadelphia, PA.
The G protein-coupled 7 transmembrane (STM) chemoattractant
receptors can be inactivated by heterologous desensitization. Earlier
work showed that formly peptide receptor-like 1 (FPRL1), an STM
receptor with low affinity for the bacterial chemotactic peptide
formyl-methionyl-leucyl-phenylalamine (fMLF), is activated by
peptide domains derived from the human immunodeficiency virus (HIV)-1
envelope glycoprotein gp120 and its activation results in
desensitization and down-regulation of the chemokine receptors CCR5 and
CXCR4 from monocyte surfaces. This study investigated the possibility
of interfering with the function of CCR5 or CXCR4 as HIV-1 coreceptors
by activating FPRL1. Cell lines were established expressing FPRL1 in
combination with CD4/CXCR4 or CD4/CCR5 and the effect of a synthetic
peptide, WKYMVm, a potent activator of formyl peptide receptors with
preference for FPRL1 was determined. Both CXCR4 and CCR5 were
desensitized by activation of the cells with WKYMVm via a
staurosporine-sensitive pathway. This desensitization of CXCR4 and CCR5
also attenuated their capacity as the fusion cofactors for HIV-1
envelope glycoprotein and resulted in a significant inhibition of p24
production by cell lines infected with HIV-1 that use CCR5 or CXCR4 as
coreceptors. Furthermore, WKYMVm inhibited the infection of human
peripheral monocyte-derived macrophages and CD4+ T
lymphocytes by R5 or X4 strains of HIV-1, respectively. These results
indicate that heterologous desensitization of CCR5 and CXCR4 by an
FPRL1 agonist attenuates their major biologic functions and suggest an
approach to the development of additional anti-HIV-1 agents.
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