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

Abstract

Progressive quantitative and qualitative decline of CD4+ T cell responses is one hallmark of HIV-1 infection and likely depends on several factors, including a possible contribution by the HIV-1 envelope glycoprotein gp120, which binds with high affinity to the CD4 receptor. Besides virion-associated and cell-expressed gp120, considerable amounts of soluble gp120 are found in plasma or lymphoid tissue, predominantly in the form of gp120–anti-gp120 immune complexes (ICs). Because the functional consequences of gp120 binding to CD4+ T cells are controversially discussed, we investigated how gp120 affects TCR-mediated activation of human CD4+ T cells by agonistic anti-CD3 mAb or by HLA class II–presented peptide Ags. We show that the spatial orientation of gp120–CD4 receptor binding relative to the site of TCR engagement differentially affects TCR signaling efficiency and hence CD4+ T cell activation. Whereas spatially and temporally linked CD4 and TCR triggering at a defined site promotes CD4+ T cell activation by exceeding local thresholds for signaling propagation, CD4 receptor engagement by gp120-containing ICs all around the CD4+ T cell undermine its capacity in supporting proximal TCR signaling. In vitro, gp120 ICs are efficiently captured by CD4+ T cells and thereby render them hyporesponsive to TCR stimulation. Consistent with these in vitro results we show that CD4+ T cells isolated from HIV+ individuals are covered with ICs, which at least partially contain gp120, and suggest that IC binding to CD4 receptors might contribute to the progressive decline of CD4+ T cell function during HIV-1 infection.

HIV Envelope gp120 Alters T Cell Receptor Mobilization in the Immunological Synapse of Uninfected CD4 T Cells and Augments T Cell Activation

“…These results are in concordance with a previous report by Zimmermann et al (62) showing that simultaneous engagement of TCR by anti-CD3 antibody and CD4 by the HIV Env boosted CD4 T cell activation. In contrast, the interaction of CD4 T cells with soluble HIV gp120 retarded TCR-induced proliferation.…”

“…In contrast, the interaction of CD4 T cells with soluble HIV gp120 retarded TCR-induced proliferation. HIV Env-CD4 interactions that occurred separately prior to TCR engagement were also found to undermine TCR-proximal signaling and downstream activation events (62). Similarly, pre-engagement of CD4 by HIV, followed by treatment with anti-CD3/ CD28-coated beads, resulted in inhibition of Lck and F-actin recruitment to T cell immunological synapses (49).…”

Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site

“…A growing number of studies have confirmed that gp120 alone or immune complexed with antibodies is likely to decrease CD4 T-cell function ( 13 ). HIV-1 replication is associated not only with virion-bound Env glycoprotein but also with shedding of soluble gp120 or gp160 during replication in vivo ( 14 , 15 ).…”

“…A number of studies have demonstrated that gp120 binding to the CD4 receptor interferes with normal T-cell receptor (TCR)-induced CD4 + T cell activation ( 19 – 21 ). The recent confirmation that gp120-immune complexes also engaged CD4 receptors and prevented subsequent TCR-mediated activation of CD4 + T cells has raised concerns over immunization with HIV envelope ( 13 ).…”

Virtual Screening, Biological Evaluation, and 3D-QSAR Studies of New HIV-1 Entry Inhibitors That Function via the CD4 Primary Receptor

“…CD4, as the primary receptor of the HIV-1 envelope glycol protein 120 (gp120), is critical for HIV-1 entry into host cells [ 9 , 10 ]. HIV-1 infection is initiated by the binding and attachment of gp120 to CD4 [ 11 ], which induces a series of conformational changes in gp120 that consequently expose its third variable (V3) loop for specific recognition of a coreceptor, either CCR5 or CXCR4 [ 12 , 13 , 14 ]. Coreceptor binding is the second obligatory event in HIV-1 entry, and it can specifically determine the tropism of HIV-1 infection [ 15 , 16 ].…”