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Published May 4, 2017 | Supplemental Material + Published
Journal Article Open

Predicting HIV-1 transmission and antibody neutralization efficacy in vivo from stoichiometric parameters

Abstract

The potential of broadly neutralizing antibodies targeting the HIV-1 envelope trimer to prevent HIV-1 transmission has opened new avenues for therapies and vaccines. However, their implementation remains challenging and would profit from a deepened mechanistic understanding of HIV-antibody interactions and the mucosal transmission process. In this study we experimentally determined stoichiometric parameters of the HIV-1 trimer-antibody interaction, confirming that binding of one antibody is sufficient for trimer neutralization. This defines numerical requirements for HIV-1 virion neutralization and thereby enables mathematical modelling of in vitro and in vivo antibody neutralization efficacy. The model we developed accurately predicts antibody efficacy in animal passive immunization studies and provides estimates for protective mucosal antibody concentrations. Furthermore, we derive estimates of the probability for a single virion to start host infection and the risks of male-to-female HIV-1 transmission per sexual intercourse. Our work thereby delivers comprehensive quantitative insights into both the molecular principles governing HIV-antibody interactions and the initial steps of mucosal HIV-1 transmission. These insights, alongside the underlying, adaptable modelling framework presented here, will be valuable for supporting in silico pre-trial planning and post-hoc evaluation of HIV-1 vaccination or antibody treatment trials.

Additional Information

© 2017 Brandenberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: November 8, 2016; Accepted: March 24, 2017; Published: May 4, 2017. We thank Dr. Dennis Burton and Dr. Brian Moldt for providing original data of in vitro SHIV-P3 neutralization by nAbs PGT121, PGT126 and b12 [10, 16]. We thank Dr. Olga T. Schubert for helpful discussions and comments on the manuscript and Jacqueline Weber and Therese Uhr for excellent technical assistance. Financial support for this study was provided by the Swiss National Science Foundation (http://www.snf.ch; grants 314730_152663 to AT, 31003A_149769 to RRR and 324730_159868 to HFG), the University of Zurich's Clinical Research Priority Program: Viral Infectious Diseases (http://www.uzh.ch/en/research/medicine/clinic.html; to AT and HFG), the Swiss Vaccine Research Institute (http://www.swissvaccineresearchinstitute.ch; to AT, HFG and RRR), a SystemsX.ch grant (http://www.antibodyx.org; AntibodyX to AT and RRR) and a grant from the Deutsche Forschungsgemeinschaft (http://www.dfg.de/; BR 5238/1-1 to OFB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Author Contributions: Conceptualization: OFB CM RRR AT. Data curation: PR CM. Formal analysis: OFB CM PR RRR. Funding acquisition: AT HFG RRR OFB. Investigation: OFB PR CM. Methodology: OFB PR CM RRR AT. Project administration: AT. Resources: HG AT. Supervision: AT. Validation: OFB PR CM RRR AT. Visualization: OFB CM. Writing – original draft: OFB CM AT. Writing – review & editing: OFB CM AT HFG PR RRR. The authors have declared that no competing interests exist.

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Supplemental Material - 4974884.zip

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August 19, 2023
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