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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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Related in: MedlinePlus

Kinetic neutralisation curves for different spike number distributions.Binding constants are all , dissociation constants are all , the stoichiometry of entry is  and the stoichiometry of trimer neutralisation is . Red curves have a spike number distribution with mean 10, where all virions in the case of the dashed line have exactly 10 spikes and in case of the dotted lines have an equal probability to have 2,3…, 18 spikes. The black curve underlies the HIV specific discretised Beta distribution with mean 14 and variance 49. The spike number distributions for the blue curves have mean 36, where the one for the dashed line has only virions expressing 36 spikes and the dotted line has 0–72 spikes.
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pcbi-1002900-g006: Kinetic neutralisation curves for different spike number distributions.Binding constants are all , dissociation constants are all , the stoichiometry of entry is and the stoichiometry of trimer neutralisation is . Red curves have a spike number distribution with mean 10, where all virions in the case of the dashed line have exactly 10 spikes and in case of the dotted lines have an equal probability to have 2,3…, 18 spikes. The black curve underlies the HIV specific discretised Beta distribution with mean 14 and variance 49. The spike number distributions for the blue curves have mean 36, where the one for the dashed line has only virions expressing 36 spikes and the dotted line has 0–72 spikes.

Mentions: Our model (equations 2 and 6) is formulated with enough flexibility that we can account for variation in trimer number distribution and variation in binding sites within a trimer. However, we only test the effect of variation in the trimer number distribution here. In Figure 6 we show the kinetic neutralisation curves for different viral populations. Curves in red are based on virions with a mean trimer number distribution of 10, black 14 and blue 36. The higher the trimer number is, the slower neutralisation happens. This means the more spikes a virion expresses, the more antibodies must bind for neutralisation. The dashed red line and the dashed blue line are based on virions with exactly 10 and 36 spikes, respectively. The dotted red line is based on spike numbers varying from 2 to 18 and the dotted blue line 0–72 spikes. Comparing the dotted and the dashed lines, one sees that variation in spike numbers has an effect on the kinetic neutralisation curves. However, more variation in spike numbers does not necessarily means slower neutralisation.


Virus neutralisation: new insights from kinetic neutralisation curves.

Magnus C - PLoS Comput. Biol. (2013)

Kinetic neutralisation curves for different spike number distributions.Binding constants are all , dissociation constants are all , the stoichiometry of entry is  and the stoichiometry of trimer neutralisation is . Red curves have a spike number distribution with mean 10, where all virions in the case of the dashed line have exactly 10 spikes and in case of the dotted lines have an equal probability to have 2,3…, 18 spikes. The black curve underlies the HIV specific discretised Beta distribution with mean 14 and variance 49. The spike number distributions for the blue curves have mean 36, where the one for the dashed line has only virions expressing 36 spikes and the dotted line has 0–72 spikes.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1002900-g006: Kinetic neutralisation curves for different spike number distributions.Binding constants are all , dissociation constants are all , the stoichiometry of entry is and the stoichiometry of trimer neutralisation is . Red curves have a spike number distribution with mean 10, where all virions in the case of the dashed line have exactly 10 spikes and in case of the dotted lines have an equal probability to have 2,3…, 18 spikes. The black curve underlies the HIV specific discretised Beta distribution with mean 14 and variance 49. The spike number distributions for the blue curves have mean 36, where the one for the dashed line has only virions expressing 36 spikes and the dotted line has 0–72 spikes.
Mentions: Our model (equations 2 and 6) is formulated with enough flexibility that we can account for variation in trimer number distribution and variation in binding sites within a trimer. However, we only test the effect of variation in the trimer number distribution here. In Figure 6 we show the kinetic neutralisation curves for different viral populations. Curves in red are based on virions with a mean trimer number distribution of 10, black 14 and blue 36. The higher the trimer number is, the slower neutralisation happens. This means the more spikes a virion expresses, the more antibodies must bind for neutralisation. The dashed red line and the dashed blue line are based on virions with exactly 10 and 36 spikes, respectively. The dotted red line is based on spike numbers varying from 2 to 18 and the dotted blue line 0–72 spikes. Comparing the dotted and the dashed lines, one sees that variation in spike numbers has an effect on the kinetic neutralisation curves. However, more variation in spike numbers does not necessarily means slower neutralisation.

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