The orientation of HIV-1 gp120 binding to the CD4 receptor differentially modulates CD4+ T cell activation

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.