Synergism Between HIV gp120 and gp120-Specific Antibody in Blocking Human T Cell Activation

Abstract

The human immunodeficiency virus (HIV) binds to CD4-positive cells through interaction of its envelope glycoprotein (gp120) with the CD4 molecule. CD4 is a prominent immunoregulatory molecule, and chronic exposure to antibody against CD4 (anti-CD4) has been shown to cause immunodeficiency in mice. T cell-dependent in vitro immune responses can also be inhibited by anti-CD4. Experimental findings reported here indicate that CD4-bound gp120 attracts gp120-specific antibodies derived from the blood of HIV-seropositive individuals to form a trimolecular complex with itself and CD4. Thus targeted to CD4, the gp120-specific antibody functions as an antibody to CD4; it cross-links and modulates the CD4 molecules and suppresses the activation of T cells as measured by mobilization of intracellular calcium (Ca2i+). The synergism between gp120 and anti-gp120 in blocking T cell activation occurs at low concentrations of both components. Neither gp120 nor anti-gp120 inhibits T cell activation by itself in the concentrations tested.

The Orientation of HIV-1 gp120 Binding to the CD4 Receptor Differentially Modulates CD4+ T Cell Activation

“…CD4 receptors play a crucial role in enhancing sensitivity of TCR-triggered T cell activation by interacting with MHC class II (MHC II) molecules on APCs (25,26) and by their noncovalent interaction with the src family tyrosine kinase p56 lck whose activation initiates TCR signaling progression (26)(27)(28)(29). In line with this, a plethora of in vitro studies provide experimental proof that gp120 binding to the CD4 receptor interferes with TCR-induced CD4 + T cell activation (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). However, the effect of noninfectious gp120-CD4 receptor interaction on CD4 + T cell activation is still a contradictory issue in the literature, and the gp120 levels measured in plasma of HIV + patients may be below those that have functional effects on cells in vitro (48).…”

“…Such direct interference with the function of central regulators of the immune system is unique among human persistent viruses and represents a crucial factor in undermining HIV-specific and heterologous immune control. CD4 receptor binding by the HIV-1 envelope mediates not only viral infection (11,12), but it can also amplify TCR-induced signaling by recruiting p56 lck to the engaged TCRs (26-29, 89, 90), attributing the noninfectious interaction between gp120 and the CD4 receptor a potential role in modulating CD4 + T cell responses [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47]. Several studies demonstrated the presence of soluble gp120 in the plasma or lymphoid tissue of HIV-1 patients (20)(21)(22)(23)(24), but its effect on TCR-induced CD4 + T cell activation is still a contentious issue in the literature.…”

“…On the other hand, gp120 binding to CD4 + T cells was shown to reduce their activation mediated through TCR stimulation (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Mechanisms to explain gp120-induced negative effects on CD4 + T cell activation are manifold: gp120-mediated cross-linking of CD4 receptors was suggested to induce CD4 receptor endocytosis (33,35,36,41,46), to prevent peptide-MHC II-CD4 receptor interaction (37,50) through interference of gp120 with the MHC II binding site on the CD4 receptor (51), to abolish proximal TCR signaling (32,34,38,40,52), or to redistribute p56 lck away from TCRs or from the immunological synapse (IS) (39,53).…”

Inhibitory activity of HIV envelope gp120 dominates over its antigenicity for human T cells

“…This has been reported by several authors in different experimental systems [7][8][9][10][11][12][13][14][15] and recently reviewed by us [31]. Furthermore, "pretreatment of CD4+ antigen-specific T cells with soluble gpl20 enhances its inhibitory effect for antigendriven proliferation [32].…”

“…The antigen-specific response ofthe CD4+ T lymphocyte subset is MHC class II restricted [1], Interaction between CD4 and MHC Class II facilitates functional association between T lymphocytes and the antigen-presenting cells (APC) and enhances T cell receptor interaction with the presented peptide antigen [2,3], The envelope glycoprotein of HIV-1, gpl60, is composed of two moieties, gpl20 and gp41, one of which (gpl20) binds CD4 with high affinity [4], Interaction between gpl20 and CD4 accounts for the cellular tropism of the HIV-1 retrovirus [5,6], Antigen-specific activation ofT cells restricted to MHC class II can be prevented by the interaction of gpl20 with CD4, as well as by MoAb which block both MHC class II-CD4 association and gpl20-CD4 binding [7][8][9][10][11][12][13][14][15],…”