       Document 0521
 DOCN  M9590521
 TI    HIV-1 glycoprotein gp120 disrupts CD4-p56lck/CD3-T cell receptor
       interactions and inhibits CD3 signaling.
 DT    9509
 AU    Hubert P; Bismuth G; Korner M; Debre P; Laboratoire d'Immunologie
       Cellulaire et Tissulaire, CNRS URA 625,; Paris, France.
 SO    Eur J Immunol. 1995 May;25(5):1417-25. Unique Identifier : AIDSLINE
       MED/95293043
 AB    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.
 DE    Antibodies, Monoclonal/PHARMACOLOGY  Antigens,
       CD3/*IMMUNOLOGY/METABOLISM  Antigens, CD4/*IMMUNOLOGY/METABOLISM  Clone
       Cells  Human  HIV Antibodies/PHARMACOLOGY  HIV Envelope Protein
       gp120/IMMUNOLOGY/*PHARMACOLOGY  HIV-1/*IMMUNOLOGY  Kinetics  Lymphocyte
       Transformation/*DRUG EFFECTS  Phosphoproteins/METABOLISM
       Phosphorylation  Protein Processing, Post-Translational  Proto-Oncogene
       Proteins/*IMMUNOLOGY/METABOLISM  Receptor-CD3 Complex, Antigen,
       T-Cell/*IMMUNOLOGY/METABOLISM  Signal Transduction/*DRUG EFFECTS
       Support, Non-U.S. Gov't  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

