A synthetic peptide derived from human immunodeficiency virus type 1 gp120 downregulates 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 type 1 (HIV-1) downregulates the expression and function of a variety of chemoattractant receptors through a process of heterologous desensitization, we investigated whether epitopes derived from gp120 could mimic the effect. A synthetic peptide domain, designated F peptide, corresponding to amino acid residues 414-434 in the V4-C4 region of gp120 of the HIV-1 Bru strain, potently reduced monocyte binding and chemotaxis response to macrophage inflammatory protein 1beta (MIP-1beta) and stromal cell-derived factor 1alpha (SDF-1alpha), chemokines that use the receptors CCR5 and CXCR4, respectively. Further study showed that F peptide by itself is an inducer of chemotaxis and calcium mobilization in human monocytes and neutrophils. In cross-desensitization experiments, among the numerous chemoattractants tested, only the bacterial chemotactic peptide fMLF, when used at high concentrations, partially attenuated calcium mobilization induced by F peptide in phagocytes, suggesting that this peptide domain might share a 7-transmembrane, G-protein-coupled receptor with fMLF. By using cells transfected with cDNAs encoding receptors that interact with fMLF, we found that F peptide uses an fMLF receptor variant, FPRL1, as a functional receptor. The activation of monocytes by F peptide resulted in downregulation of the cell surface expression 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 activation of innate immune responses in HIV-1-infected patients followed by immune suppression.
Deng
X
X
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, Intramural Research Support Program, SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD, USA.
Ueda
H
H
Su
S B
SB
Gong
W
W
Dunlop
N M
NM
Gao
J L
JL
Murphy
P M
PM
Wang
J M
JM
D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000276:immunology*; D000595:Amino Acid Sequence; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007165:Immunosuppression Therapy; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology* / Q000821:virology*; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000276:immunology; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
C105101:FPR2 protein, human; D015699:HIV Envelope Protein gp120; D010455:Peptides; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide; D019204:GTP-Binding Proteins