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


Zimmermann, Kathrin; Liechti, Thomas; Haas, Anna; Rehr, Manuela; Trkola, Alexandra; Günthard, Huldrych F; Oxenius, Annette (2015). The orientation of HIV-1 gp120 binding to the CD4 receptor differentially modulates CD4+ T cell activation. Journal of Immunology, 194(2):637-649.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2015
Deposited On:04 Feb 2015 14:01
Last Modified:05 Apr 2016 18:47
Publisher:American Association of Immunologists
ISSN:0022-1767
Funders:Swiss Federal Institute of Technology Zurich, Swiss National Science Foundation Grant 310030_129751 (to A.O.), University of Zurich, Clinical Research Priority Program “Viral Infectious Diseases: Zurich Primary HIV Infection Study” (to H.F.G.), Horten Foundation
Publisher DOI:https://doi.org/10.4049/jimmunol.1401863
PubMed ID:25472996

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