title: 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.
authors.affiliation: Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland;
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Institute of Medical Virology, University of Zurich, 8006 Zurich, Switzerland; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Liechti
authors.affiliation: Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland;
authors.forename: Anna
authors.initials: A
authors.lastname: Haas
authors.affiliation: Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland;
authors.forename: Manuela
authors.initials: M
authors.lastname: Rehr
authors.affiliation: Institute of Medical Virology, University of Zurich, 8006 Zurich, Switzerland; and.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trkola
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.affiliation: Institute of Microbiology, Swiss Federal Institute of Technology Zurich, 8093 Zurich, Switzerland;
authors.forename: Annette
authors.initials: A
authors.lastname: Oxenius
mesh_terms: D017951:Antigen Presentation; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; C514793:gp120 protein, Human immunodeficiency virus 1