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Open Access

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

Kathrin Zimmermann, Thomas Liechti, Anna Haas, Manuela Rehr, Alexandra Trkola, Huldrych F. Günthard and Annette Oxenius
J Immunol December 3, 2014, 1401863; DOI: https://doi.org/10.4049/jimmunol.1401863
Kathrin Zimmermann
Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland;
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Thomas Liechti
Institute of Medical Virology, University of Zurich, 8006 Zurich, Switzerland; and
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Anna Haas
Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland;
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Manuela Rehr
Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland;
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Alexandra Trkola
Institute of Medical Virology, University of Zurich, 8006 Zurich, Switzerland; and
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Huldrych F. Günthard
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
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Annette Oxenius
Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland;
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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.

Footnotes

  • K.Z. and A.O. designed the experiments; K.Z., T.L., A.H., and M.R. performed experiments and analyzed data; K.Z. and A.O. discussed data; A.T. and T.L. contributed plasma samples and anti-gp120 Abs; H.F.G. enrolled patients; and K.Z. and A.O. made the figures and wrote the manuscript.

  • This work was supported by Swiss Federal Institute of Technology Zurich/Swiss National Science Foundation Grant 310030_129751 (to A.O.), the University of Zurich’s Clinical Research Priority Program “Viral Infectious Diseases: Zurich Primary HIV Infection Study” (to H.F.G.), and the Horten Foundation.

  • Received July 21, 2014.
  • Accepted November 2, 2014.
  • Copyright © 2014 by The American Association of Immunologists, Inc.

This article is distributed under The American Association of Immunologists, Inc., Reuse Terms and Conditions for Author Choice articles.

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The Journal of Immunology: 200 (8)
The Journal of Immunology
Vol. 200, Issue 8
15 Apr 2018
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The Orientation of HIV-1 gp120 Binding to the CD4 Receptor Differentially Modulates CD4+ T Cell Activation
Kathrin Zimmermann, Thomas Liechti, Anna Haas, Manuela Rehr, Alexandra Trkola, Huldrych F. Günthard, Annette Oxenius
The Journal of Immunology December 3, 2014, 1401863; DOI: 10.4049/jimmunol.1401863

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The Orientation of HIV-1 gp120 Binding to the CD4 Receptor Differentially Modulates CD4+ T Cell Activation
Kathrin Zimmermann, Thomas Liechti, Anna Haas, Manuela Rehr, Alexandra Trkola, Huldrych F. Günthard, Annette Oxenius
The Journal of Immunology December 3, 2014, 1401863; DOI: 10.4049/jimmunol.1401863
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