Inhibition of tyrosine kinase activation blocks the down-regulation of CXC chemokine receptor 4 by HIV-1 gp120 in CD4+ T cells

J Immunol. 1999 Jun 15;162(12):7128-32.

Abstract

Because the binding of HIV-1 envelope to CD4 initiates a configurational change in glycoprotein 120 (gp120), enabling it to interact with fusion coreceptors, we investigated how this process interferes with the expression and function of CXC chemokine receptor 4 (CXCR4) in CD4+ T lymphocytes. A recombinant gp120 (MN), after preincubation with CD4+ T lymphocytes, significantly inhibited the binding and chemotaxis of the cells in response to the CXCR4 ligand stromal cell-derived factor-1alpha (SDF-1alpha), accompanied by a markedly reduced surface expression of CXCR4. gp120, but not SDF-1alpha, induced rapid tyrosine phosphorylation of src-like kinase p56lck in CD4+ T cells, whereas both gp120 and SDF-1alpha caused phosphorylation of the CXCR4. The tyrosine kinase inhibitor herbimycin A abolished the phosphorylation of p56lck and CXCR4 induced by gp120 in association with maintenance of normal expression of cell surface CXCR4 and a migratory response to SDF-1alpha. Thus, a CD4-associated signaling molecule(s) including p56lck is activated by gp120 and is required for the down-regulation of CXCR4.

MeSH terms

  • Benzoquinones
  • CD4 Antigens / physiology
  • CD4-Positive T-Lymphocytes / enzymology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / physiology
  • Cell Migration Inhibition
  • Cells, Cultured
  • Chemotaxis, Leukocyte / drug effects
  • Down-Regulation / drug effects
  • Down-Regulation / immunology*
  • Enzyme Activation / drug effects
  • Enzyme Activation / immunology
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / pharmacology*
  • HIV-1 / immunology*
  • Humans
  • Lactams, Macrocyclic
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / metabolism
  • Phosphorylation / drug effects
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Quinones / pharmacology
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / metabolism
  • Recombinant Proteins / pharmacology
  • Rifabutin / analogs & derivatives
  • Tumor Cells, Cultured

Substances

  • Benzoquinones
  • CD4 Antigens
  • Enzyme Inhibitors
  • HIV Envelope Protein gp120
  • Lactams, Macrocyclic
  • Quinones
  • Receptors, CXCR4
  • Recombinant Proteins
  • Rifabutin
  • herbimycin
  • Protein-Tyrosine Kinases
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)