Abstract
T-20, a synthetic peptide corresponding to the heptad repeat sequence of HIV-1 gp41, blocks HIV-1 entry by targeting gp41, and is currently in clinical trials as an anti-retroviral agent. We recently reported that in vitro T-20 also functions as a phagocyte chemoattractant and a chemotactic agonist at the phagocyte N-formylpeptide receptor (FPR). Here we show that T-20 is also a potent chemotactic agonist in vitro at a related human phagocyte receptor FPRL1R. To test the relative importance of FPR and FPRL1R in primary cells, we identified the corresponding mouse T-20 receptors, mFPR and FPR2, which are both expressed in neutrophils, and compared T-20 action on neutrophils from wild type and mFPR knockout mice. Surprisingly, although T-20 activates mFPR and FPR2 in transfected cells with equal potency and efficacy in both calcium flux and chemotaxis assays, neutrophils from mFPR knockout mice did not respond to T-20. These results provide genetic evidence that FPR is the major phagocyte T-20 receptor in vivo and point to the potential feasibility of studying T-20 effects on immunity in a mouse model. This may help define the cause of local inflammation after T-20 injection that has recently been reported in Phase I clinical trials.
Copyright 2000 Academic Press.
MeSH terms
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Animals
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Anti-HIV Agents / adverse effects
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology*
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Calcium / metabolism
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Calcium Signaling / drug effects
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Cell Line
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Chemotaxis, Leukocyte / drug effects*
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Chemotaxis, Leukocyte / immunology
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Dose-Response Relationship, Drug
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Enfuvirtide
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HIV Envelope Protein gp41 / adverse effects
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HIV Envelope Protein gp41 / chemistry
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HIV Envelope Protein gp41 / pharmacology*
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Humans
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Inflammation / chemically induced
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Mice
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Mice, Knockout
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Multigene Family / genetics
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N-Formylmethionine Leucyl-Phenylalanine / pharmacology
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Neutrophil Activation / drug effects*
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Neutrophil Activation / immunology
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Neutrophils / cytology
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Neutrophils / drug effects*
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Neutrophils / immunology
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Neutrophils / metabolism
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Peptide Fragments / adverse effects
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Peptide Fragments / chemistry
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Peptide Fragments / pharmacology*
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Receptors, Formyl Peptide
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Receptors, Immunologic / agonists
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Receptors, Immunologic / deficiency
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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Receptors, Peptide / agonists
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Receptors, Peptide / deficiency
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Receptors, Peptide / genetics
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Receptors, Peptide / metabolism*
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Transfection
Substances
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Anti-HIV Agents
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HIV Envelope Protein gp41
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Peptide Fragments
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Receptors, Formyl Peptide
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Receptors, Immunologic
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Receptors, Peptide
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Enfuvirtide
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N-Formylmethionine Leucyl-Phenylalanine
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Calcium