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


Brandenberg, Oliver F; Magnus, Carsten; Rusert, Peter; Günthard, Huldrych F; Regoes, Roland Robert; Trkola, Alexandra (2017). Predicting HIV-1 transmission and antibody neutralization efficacy in vivo from stoichiometric parameters. PLoS Pathogens, 13(5):e1006313.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Virology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:4 May 2017
Deposited On:08 Aug 2017 15:38
Last Modified:08 Aug 2017 15:47
Publisher:Public Library of Science (PLoS)
ISSN:1553-7366
Funders:Swiss National Science Foundation (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 (to AT and HFG), The Swiss Vaccine Research Institute (to AT, HFG and RRR), SystemsX.ch grant (AntibodyX to AT and RRR), Deutsche Forschungsgemeinschaft (BR 5238/1-1 to OFB)
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1371/journal.ppat.1006313
PubMed ID:28472201
Other Identification Number:PMC5417720

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Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)

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