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Viruses 2019, 11(2), 153; https://doi.org/10.3390/v11020153

Glycosylation of HIV Env Impacts IgG Subtype Responses to Vaccination

1
Department of Molecular and Medical Virology, Ruhr-University Bochum, 44801 Bochum, Germany
2
Institute of Clinical and Molecular Virology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germany; Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany
3
Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany
4
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany
5
Immunology Unit & Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine (TiHo) Hannover, 30559 Hannover, Germany
6
Ichor Medical Systems, Inc., San Diego, CA 92121, USA
*
Author to whom correspondence should be addressed.
Contributed equally and share senior authorship.
Received: 22 January 2019 / Revised: 6 February 2019 / Accepted: 10 February 2019 / Published: 13 February 2019
(This article belongs to the Special Issue The Glycobiology of Viral Infections)
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Abstract

The envelope protein (Env) is the only surface protein of the human immunodeficiency virus (HIV) and as such the exclusive target for protective antibody responses. Experimental evidences from mouse models suggest a modulating property of Env to steer antibody class switching towards the less effective antibody subclass IgG1 accompanied with strong TH2 helper responses. By simple physical linkage we were able to imprint this bias, exemplified by a low IgG2a/IgG1 ratio of antigen-specific antibodies, onto an unrelated antigen, namely the HIV capsid protein p24. Here, our results indicate the glycan moiety of Env as the responsible immune modulating activity. Firstly, in Card9−/− mice lacking specific C-Type lectin responsiveness, DNA immunization significantly increased the IgG2a/IgG1 ratio for the Env-specific antibodies while the antibody response against the F-protein of the respiratory syncytial virus (RSV) serving as control antigen remained unchanged. Secondly, sequential shortening of the Env encoding sequence revealed the C2V3 domain as responsible for the strong IgG1 responses and TH2 cytokine production. Removing all potential N-glycosylation sites from the C2V3 domain by site-specific mutagenesis reversed the vaccine-induced immune response towards a Th1-dominated T-cell response and a balanced IgG2a/IgG1 ratio. Accordingly, the stretch of oligomannose glycans in the C2V3 domain of Env might mediate a specific uptake and/or signaling modus in antigen presenting cells by involving interaction with an as yet unknown C-type lectin receptor. Our results contribute to a deeper understanding of the impact of Env glycosylation on HIV antigen-specific immune responses, which will further support HIV vaccine development. View Full-Text
Keywords: HIV env; glycosylation; antibody response; vaccination HIV env; glycosylation; antibody response; vaccination
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Heß, R.; Storcksdieck genannt Bonsmann, M.; Lapuente, D.; Maaske, A.; Kirschning, C.; Ruland, J.; Lepenies, B.; Hannaman, D.; Tenbusch, M.; Überla, K. Glycosylation of HIV Env Impacts IgG Subtype Responses to Vaccination. Viruses 2019, 11, 153.

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