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 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. (Blood. 2001;97:2941-2947)
Li
B Q
BQ
Intramural Research Support Program and the Laboratory of Antiviral Drug Mechanism, NCI-Screening Technologies Branch, SAIC Frederick, MD, USA.
Wetzel
M A
MA
Mikovits
J A
JA
Henderson
E E
EE
Rogers
T J
TJ
Gong
W
W
Le
Y
Y
Ruscetti
F W
FW
Wang
J M
JM
D000998:Antiviral Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D015870:Gene Expression; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000821:virology; D018945:Monocyte Chemoattractant Proteins / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D012516:Osteosarcoma; D019713:Receptors, CCR5 / Q000187:drug effects* / Q000502:physiology; D019718:Receptors, CXCR4 / Q000187:drug effects* / Q000502:physiology; D044042:Receptors, Formyl Peptide; D015728:Receptors, HIV / Q000235:genetics; D011971:Receptors, Immunologic / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; C105101:FPR2 protein, human; D015699:HIV Envelope Protein gp120; D018945:Monocyte Chemoattractant Proteins; D009842:Oligopeptides; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D044042:Receptors, Formyl Peptide; D015728:Receptors, HIV; D011971:Receptors, Immunologic; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide; C113617:Trp-Lys-Tyr-Met-Val-Met