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Virus neutralisation: new insights from kinetic neutralisation curves.

Magnus C - PLoS Comput. Biol. (2013)

Bottom Line: Early models are based on chemical binding kinetics.This framework is in agreement with published data on the neutralisation of the human immunodeficiency virus.Knowing antibody reaction constants, our model allows us to estimate stoichiometrical parameters from kinetic neutralisation curves.

View Article: PubMed Central - PubMed

Affiliation: Institute for Emerging Infections, Department of Zoology, University of Oxford, Oxford, United Kingdom. carsten.magnus@zoo.ox.ac.uk

ABSTRACT
Antibodies binding to the surface of virions can lead to virus neutralisation. Different theories have been proposed to determine the number of antibodies that must bind to a virion for neutralisation. Early models are based on chemical binding kinetics. Applying these models lead to very low estimates of the number of antibodies needed for neutralisation. In contrast, according to the more conceptual approach of stoichiometries in virology a much higher number of antibodies is required for virus neutralisation by antibodies. Here, we combine chemical binding kinetics with (virological) stoichiometries to better explain virus neutralisation by antibody binding. This framework is in agreement with published data on the neutralisation of the human immunodeficiency virus. Knowing antibody reaction constants, our model allows us to estimate stoichiometrical parameters from kinetic neutralisation curves. In addition, we can identify important parameters that will make further analysis of kinetic neutralisation curves more valuable in the context of estimating stoichiometries. Our model gives a more subtle explanation of kinetic neutralisation curves in terms of single-hit and multi-hit kinetics.

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Influence of reaction parameters on the feasibility of estimating the stoichiometry of neutralisation,. The concentration of spikes and antibodies is the same for all graphs, i.e.  and  and the stoichiometry of entry is . (A) All binding constants have the same value  and all dissociation have the same value . (B) Same coloured graphs correspond to the same reaction constants. Blue curves: the -complex is built preferentially, due to the reaction constants . Red curves: the -complex is built preferentially, . Green curves: the -complexes are built preferentially, . (C) The binding constants decrease and the dissociation constants increase, i.e. . Only in this case are the kinetic neutralisation curves for different stoichiometries of neutralisation distinguishable.
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pcbi-1002900-g004: Influence of reaction parameters on the feasibility of estimating the stoichiometry of neutralisation,. The concentration of spikes and antibodies is the same for all graphs, i.e. and and the stoichiometry of entry is . (A) All binding constants have the same value and all dissociation have the same value . (B) Same coloured graphs correspond to the same reaction constants. Blue curves: the -complex is built preferentially, due to the reaction constants . Red curves: the -complex is built preferentially, . Green curves: the -complexes are built preferentially, . (C) The binding constants decrease and the dissociation constants increase, i.e. . Only in this case are the kinetic neutralisation curves for different stoichiometries of neutralisation distinguishable.

Mentions: To date, the reaction constants have not been identified. However, with our model framework it is possible to derive general rules for when the estimation of stoichiometric parameters is possible. In Figure 3 (B) we showed that the variation between kinetic neutralisation curves for different stoichiometries of entry, , are quite big and therefore the estimation of this parameter may be possible. However, the reaction constants influence the ability to distinguish kinetic neutralisation curves for different stoichiometries of neutralisation, . If the binding and dissociation constants are all equal for the three binding steps, most of the spikes will be bound to three antibodies and only a few to one or two antibodies. In this case, the kinetic neutralisation curves for different stoichiometries of neutralisation are the same (see Figure 4 (A)). If the binding and dissociation constants are such that formation of one spike-antibody complex (e.g. ) is fast and the formation of the others is slow, this spike-antibody complex forms an attraction point for the overall reaction. Most of the spikes are bound to that specific number of antibodies (e.g. if forms the attraction point, almost all spikes are bound to two antibodies). Figure 4 (B) shows kinetic neutralisation curves for different attraction points. If the attraction point is , a virion population cannot be neutralised with antibodies having a - or -stoichiometry (dashed and dotted blue lines). If the attraction point is , antibodies with a - and a -stoichiometry have the same kinetic neutralisation curve (solid and dashed red line). An antibody with a - stoichiometry, however, cannot fully neutralise the virion population but the neutralisation levels off (dotted red line). If the attraction point is , the kinetic neutralisation curves for all stoichiometries are the same (solid, dashed and dotted green line). If the binding constants decrease and the association constants increase ( and ), there is a time delay in the formation of spike antibody complexes with two and three antibodies respectively. This leads to different dynamics of the kinetic neutralisation curves for different stoichiometries of neutralisation. Thus, the kinetic neutralisation curves for different stoichiometries of neutralisation are clearly distinguishable and the estimation of this stoichiometric parameter might be possible.


Virus neutralisation: new insights from kinetic neutralisation curves.

Magnus C - PLoS Comput. Biol. (2013)

Influence of reaction parameters on the feasibility of estimating the stoichiometry of neutralisation,. The concentration of spikes and antibodies is the same for all graphs, i.e.  and  and the stoichiometry of entry is . (A) All binding constants have the same value  and all dissociation have the same value . (B) Same coloured graphs correspond to the same reaction constants. Blue curves: the -complex is built preferentially, due to the reaction constants . Red curves: the -complex is built preferentially, . Green curves: the -complexes are built preferentially, . (C) The binding constants decrease and the dissociation constants increase, i.e. . Only in this case are the kinetic neutralisation curves for different stoichiometries of neutralisation distinguishable.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585397&req=5

pcbi-1002900-g004: Influence of reaction parameters on the feasibility of estimating the stoichiometry of neutralisation,. The concentration of spikes and antibodies is the same for all graphs, i.e. and and the stoichiometry of entry is . (A) All binding constants have the same value and all dissociation have the same value . (B) Same coloured graphs correspond to the same reaction constants. Blue curves: the -complex is built preferentially, due to the reaction constants . Red curves: the -complex is built preferentially, . Green curves: the -complexes are built preferentially, . (C) The binding constants decrease and the dissociation constants increase, i.e. . Only in this case are the kinetic neutralisation curves for different stoichiometries of neutralisation distinguishable.
Mentions: To date, the reaction constants have not been identified. However, with our model framework it is possible to derive general rules for when the estimation of stoichiometric parameters is possible. In Figure 3 (B) we showed that the variation between kinetic neutralisation curves for different stoichiometries of entry, , are quite big and therefore the estimation of this parameter may be possible. However, the reaction constants influence the ability to distinguish kinetic neutralisation curves for different stoichiometries of neutralisation, . If the binding and dissociation constants are all equal for the three binding steps, most of the spikes will be bound to three antibodies and only a few to one or two antibodies. In this case, the kinetic neutralisation curves for different stoichiometries of neutralisation are the same (see Figure 4 (A)). If the binding and dissociation constants are such that formation of one spike-antibody complex (e.g. ) is fast and the formation of the others is slow, this spike-antibody complex forms an attraction point for the overall reaction. Most of the spikes are bound to that specific number of antibodies (e.g. if forms the attraction point, almost all spikes are bound to two antibodies). Figure 4 (B) shows kinetic neutralisation curves for different attraction points. If the attraction point is , a virion population cannot be neutralised with antibodies having a - or -stoichiometry (dashed and dotted blue lines). If the attraction point is , antibodies with a - and a -stoichiometry have the same kinetic neutralisation curve (solid and dashed red line). An antibody with a - stoichiometry, however, cannot fully neutralise the virion population but the neutralisation levels off (dotted red line). If the attraction point is , the kinetic neutralisation curves for all stoichiometries are the same (solid, dashed and dotted green line). If the binding constants decrease and the association constants increase ( and ), there is a time delay in the formation of spike antibody complexes with two and three antibodies respectively. This leads to different dynamics of the kinetic neutralisation curves for different stoichiometries of neutralisation. Thus, the kinetic neutralisation curves for different stoichiometries of neutralisation are clearly distinguishable and the estimation of this stoichiometric parameter might be possible.

Bottom Line: Early models are based on chemical binding kinetics.This framework is in agreement with published data on the neutralisation of the human immunodeficiency virus.Knowing antibody reaction constants, our model allows us to estimate stoichiometrical parameters from kinetic neutralisation curves.

View Article: PubMed Central - PubMed

Affiliation: Institute for Emerging Infections, Department of Zoology, University of Oxford, Oxford, United Kingdom. carsten.magnus@zoo.ox.ac.uk

ABSTRACT
Antibodies binding to the surface of virions can lead to virus neutralisation. Different theories have been proposed to determine the number of antibodies that must bind to a virion for neutralisation. Early models are based on chemical binding kinetics. Applying these models lead to very low estimates of the number of antibodies needed for neutralisation. In contrast, according to the more conceptual approach of stoichiometries in virology a much higher number of antibodies is required for virus neutralisation by antibodies. Here, we combine chemical binding kinetics with (virological) stoichiometries to better explain virus neutralisation by antibody binding. This framework is in agreement with published data on the neutralisation of the human immunodeficiency virus. Knowing antibody reaction constants, our model allows us to estimate stoichiometrical parameters from kinetic neutralisation curves. In addition, we can identify important parameters that will make further analysis of kinetic neutralisation curves more valuable in the context of estimating stoichiometries. Our model gives a more subtle explanation of kinetic neutralisation curves in terms of single-hit and multi-hit kinetics.

Show MeSH
Related in: MedlinePlus