T21/DP107, A synthetic leucine zipper-like domain of the HIV-1 envelope gp41, attracts and activates human phagocytes by using G-protein-coupled formyl peptide receptors.
A leucine zipper-like domain, T21/DP107, located in the amino terminus of the ectodomain of gp41, is crucial to the formation of fusogenic configuration of the HIV-1 envelope protein gp41. We report that the synthetic T21/DP107 segment is a potent stimulant of migration and calcium mobilization in human monocytes and neutrophils. The activity of T21/DP107 on phagocytes was pertussis toxin-sensitive, suggesting this peptide uses Gi-coupled seven-transmembrane receptor(s). Since the bacterial chemotactic peptide fMLP partially desensitized the calcium-mobilizing activity of T21/DP107 in phagocytes, we postulated that T21/DP107 might preferentially use a lower affinity fMLP receptor. By using cells transfected to express cloned prototype chemotactic N-formyl peptide receptor (FPR) or its variant, FPR-like 1 (FPRL1), we demonstrate that T21/DP107 activates both receptors but has a much higher efficacy for FPRL1. In addition, T21/DP107 at nM concentrations induced migration of FPRL1-transfected human embryonic kidney 293 cells. In contrast, fMLP did not induce significant chemotaxis of the same cells at a concentration as high as 50 microM. Although a lipid metabolite, lipoxin A4, was a high-affinity ligand for FPRL1, it was not reported to induce Ca2+ mobilization or chemotaxis in FPRL1-transfected cells. Therefore, T21/DP107 is a first chemotactic peptide agonist identified thus far for FPRL1. Our results suggest that this peptide domain of the HIV-1 gp41 may have the potential to activate host innate immune response by interacting with FPR and FPRL1 on phagocytes.
Su
S B
SB
Laboratory of Molecular Immunoregulation, Division of Basic Sciences; Intramural Research Support Program, Science Applications International Corporation-Frederick, NCI-Frederick Cancer Research and Development Center, MD 21702, USA.
Gao
J l
Jl
Gong
W h
Wh
Dunlop
N M
NM
Murphy
P M
PM
Oppenheim
J J
JJ
Wang
J M
JM
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000276:immunology* / Q000494:pharmacology; D020013:Calcium Signaling; D002634:Chemotaxis, Leukocyte; D019204:GTP-Binding Proteins / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000276:immunology* / Q000494:pharmacology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D016350:Leucine Zippers / Q000276:immunology*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D010586:Phagocytes / Q000276:immunology*; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000378:metabolism; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide / Q000378:metabolism
D019380:Anti-HIV Agents; C105101:FPR2 protein, human; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D044067:Receptors, Lipoxin; D018000:Receptors, Peptide; C102014:peptide T21; D019204:GTP-Binding Proteins