Human Cytomegalovirus antagonizes activation of Fcγ receptors by distinct and synergizing modes of IgG manipulation
Human Cytomegalovirus (HCMV) is endowed with multiple highly sophisticated immune evasion strategies. This includes the evasion from antibody mediated immune control by counteracting host Fc-gamma receptor (FcγR) mediated immune control mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC). We have previously shown that HCMV avoids FcγR activation by concomitant expression of the viral Fc-gamma binding glycoproteins (vFcγRs) gp34 and gp68. We now show that gp34 and gp68 bind IgG simultaneously at topologically different Fcγ sites and achieve efficient antagonization of host FcγR activation by distinct but synergizing mechanisms. While gp34 enhances immune complex internalization, gp68 acts as inhibitor of host FcγR binding to immune complexes. In doing so, gp68 induces Fcγ accessibility to gp34 and simultaneously limits host FcγR recognition. The synergy of gp34 and gp68 is compelled by the interfering influence of excessive non-immune IgG ligands and highlights conformational changes within the IgG globular chains critical for antibody effector function.
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all pertinent Figures (Figures 1D, 3D, 4C, 5D, 6B, 6C, 6D, Figure 4-figure supplement 1)
Article and author information
Deutsche Forschungsgemeinschaft (HE2526/9-1; FOR2830)
- Hartmut Hengel
Bundesministerium für Bildung und Forschung (031L0090)
- Hartmut Hengel
Faculty of Medicine, Albert-Ludwigs-University; (EQUIP - Funding for Medical Scientists)
- Philipp Kolb
Deutsche Forschungsgemeinschaft (HA6035/2-1; FOR2830)
- Anne Halenius
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Human subjects: Consent of blood donors was approved by the ethical review committee, University of Freiburg, vote 474/18.
- Melanie M Brinkmann, Technische Universität Braunschweig, Germany
- Received: October 9, 2020
- Accepted: March 15, 2021
- Accepted Manuscript published: March 16, 2021 (version 1)
- Version of Record published: April 12, 2021 (version 2)
© 2021, Kolb et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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