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.
Highlights
Recent years have seen tremendous success in the isolation and characterization of broadly neutralizing antibodies from selected HIV-1 infected patients
Starting at the molecular level, the first question we addressed regards the number of nAbs required to neutralize each HIV-1 envelope glycoprotein trimer (Env) trimer
We (i) investigated the stoichiometric parameters of nAb binding to Env trimers on virions leading to neutralization, (ii) modelled nAb neutralization and HIV-1 infectivity both in vitro and in macaque passive nAb immunization virus challenge studies, and (iii) modelled HIV-1 transmission risk and protective effects of nAbs in the human host during penilevaginal sexual contact
Summary
Recent years have seen tremendous success in the isolation and characterization of broadly neutralizing antibodies (bnAbs) from selected HIV-1 infected patients. It is assumed that the elicitation of antibodies will constitute a crucial component of a successful HIV-1 vaccination strategy, and known bnAbs are intensely explored as templates for HIV-1 vaccine development [1,2,3,4,5] It has been conclusively demonstrated in animal models that passive immunization with bnAbs can protect against virus challenge, delay viral rebound and transiently lower viremia [6,7,8,9,10,11,12,13,14,15,16,17,18,19]. Passive immunization in human patients demonstrated an impact of bnAbs on established HIV-1 infection [20,21,22], underscoring the potential relevance of bnAbs to prevent or treat HIV-1 infection Despite this wealth of information on the protective effects of bnAbs in vivo, key parameters of the HIV-1 nAb interaction and HIV-1 host-to-host transmission remain illdefined. We propose that precise numerical quantification of the parameters that steer nAb efficacy and in vivo HIV-1 transmission is needed
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