HIV-1 glycoprotein gp120 disrupts CD4-p56lck/CD3-T cell receptor interactions and inhibits CD3 signaling

Eur J Immunol. 1995 May;25(5):1417-25. doi: 10.1002/eji.1830250542.


Using the CD4+ human T cell clone P28, we demonstrated that the HIV-1 glycoprotein gp120 inhibited CD3-induced inositol trisphosphate production, calcium influx and T cell proliferation. Additionally, gp120 was shown to dissociate the tyrosine kinase p56lck from CD4 in CEM cells, with a concommittant inhibition of CD4-linked kinase activity. We have addressed the question whether disruption of CD4/p56lck or CD4/CD3-T cell receptor interactions, or both, could account for the inhibitory effect of gp120 in P28 cells. By comparing the effects of various anti-CD4 monoclonal antibodies (mAb) with those of gp120, we show that gp120 and IOT4a modulate CD4 expression, and decrease CD4-associated p56lck and CD4-linked kinase activity at the plasma membrane. In contrast, OKT4A and OKT4 anti-CD4 mAb have no inhibitory effect. Interestingly, gp120 also inhibits CD3-induced Lck activation and cellular tyrosine phosphorylation, particularly of phosphoinositide-specific phospholipase C-gamma-1. Kinetic experiments reveal that the inhibitory effect of gp120 on CD3-induced tyrosine phosphorylation appears as early as 30 min, but culminate when CD4-p56lck complexes disappear from the cell surface after 4 h. These results suggest that a negative signal is triggered by gp120 that results, after a few hours, in down-modulation of CD4-p56lck complexes and the impairment of CD3 signaling. Supporting this hypothesis, gp120 inhibits CD3-linked kinase activity as shown by the inhibition of the phosphorylation of CD3 chains, leading to the inhibition of subsequent signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • CD3 Complex / immunology*
  • CD3 Complex / metabolism
  • CD4 Antigens / immunology*
  • CD4 Antigens / metabolism
  • Clone Cells
  • HIV Antibodies / pharmacology
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / pharmacology*
  • HIV-1 / immunology*
  • Humans
  • Kinetics
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proto-Oncogene Proteins / immunology*
  • Proto-Oncogene Proteins / metabolism
  • Receptor-CD3 Complex, Antigen, T-Cell / immunology*
  • Receptor-CD3 Complex, Antigen, T-Cell / metabolism
  • Signal Transduction / drug effects*


  • Antibodies, Monoclonal
  • CD3 Complex
  • CD4 Antigens
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Receptor-CD3 Complex, Antigen, T-Cell
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)