The HIV-1 cell entry inhibitor T-20 potently chemoattracts neutrophils by specifically activating the N-formylpeptide receptor

Biochem Biophys Res Commun. 2000 Jun 16;272(3):699-704. doi: 10.1006/bbrc.2000.2846.

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.

MeSH terms

  • Animals
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Cell Line
  • Chemotaxis, Leukocyte / drug effects*
  • Chemotaxis, Leukocyte / immunology
  • Dose-Response Relationship, Drug
  • Enfuvirtide
  • HIV Envelope Protein gp41 / adverse effects
  • HIV Envelope Protein gp41 / chemistry
  • HIV Envelope Protein gp41 / pharmacology*
  • Humans
  • Inflammation / chemically induced
  • Mice
  • Mice, Knockout
  • Multigene Family / genetics
  • N-Formylmethionine Leucyl-Phenylalanine / pharmacology
  • Neutrophil Activation / drug effects*
  • Neutrophil Activation / immunology
  • Neutrophils / cytology
  • Neutrophils / drug effects*
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Peptide Fragments / adverse effects
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Receptors, Formyl Peptide
  • Receptors, Immunologic / agonists
  • Receptors, Immunologic / deficiency
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Receptors, Peptide / agonists
  • Receptors, Peptide / deficiency
  • Receptors, Peptide / genetics
  • Receptors, Peptide / metabolism*
  • Transfection

Substances

  • Anti-HIV Agents
  • HIV Envelope Protein gp41
  • Peptide Fragments
  • Receptors, Formyl Peptide
  • Receptors, Immunologic
  • Receptors, Peptide
  • Enfuvirtide
  • N-Formylmethionine Leucyl-Phenylalanine
  • Calcium