Inhibitory mechanism of the CXCR4 antagonist T22 against human immunodeficiency virus type 1 infection

  • Murakami T
  • Zhang T
  • Koyanagi Y
 et al. 
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Abstract

We recently reported that a cationic peptide, T22 ([Tyr(5,12), Lys(7)]-polyphemusin II), specifically inhibits human immunodeficiency virus type 1 (HIV-1) infection mediated by CXCR4 (T. Murakami et al., J. Exp. Med. 186:1389-1393, 1997). Here we demonstrate that T22 effectively inhibits replication of T-tropic HIV-1, including primary isolates, but not of non-T-tropic strains. By using a panel of chimeric viruses between T- and M-tropic HIV-1 strains, viral determinants for T22 susceptibility were mapped to the V3 loop region of gp120. T22 bound to CXCR4 and interfered with stromal-cell-derived factor-1alpha-CXCR4 interactions in a competitive manner. Blocking of anti-CXCR4 monoclonal antibodies by T22 suggested that the peptide interacts with the N terminus and two of the extracellular loops of CXCR4. Furthermore, the inhibition of cell-cell fusion in cells expressing CXCR4/CXCR2 chimeric receptors suggested that determinants for sensitivity of CXCR4 to T22 include the three extracellular loops of the coreceptor.

Author-supplied keywords

  • *Antimicrobial Cationic Peptides
  • Amino Acid Sequence
  • Anti-HIV Agents/metabolism/*pharmacology
  • Binding Sites
  • Cell Fusion
  • Chemokine CXCL12
  • Chemokines, CXC/metabolism
  • HIV Envelope Protein gp120/metabolism
  • HIV-1/*drug effects/metabolism
  • HeLa Cells
  • Humans
  • Lipid Metabolism
  • Molecular Sequence Data
  • Peptide Fragments/metabolism
  • Peptides/metabolism/*pharmacology
  • Receptors, CXCR4/*antagonists & inhibitors
  • Tumor Cells, Cultured

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Authors

  • T Murakami

  • T Y Zhang

  • Y Koyanagi

  • Y Tanaka

  • J Kim

  • Y Suzuki

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