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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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Predictions for kinetic neutralisation curves for the elementary reaction model.(A) All binding constants are  and all dissociation constants are . The stoichiometry of entry is assumed to be . The starting concentration of antibodies is  and the starting concentration of trimers is . (B) Same constants as in (A) but the starting concentration of antibodies is . (C) The binding constants are  and the dissociation constants are all . The stoichiometry of entry is  and the antibody starting concentration is .
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pcbi-1002900-g002: Predictions for kinetic neutralisation curves for the elementary reaction model.(A) All binding constants are and all dissociation constants are . The stoichiometry of entry is assumed to be . The starting concentration of antibodies is and the starting concentration of trimers is . (B) Same constants as in (A) but the starting concentration of antibodies is . (C) The binding constants are and the dissociation constants are all . The stoichiometry of entry is and the antibody starting concentration is .

Mentions: The mathematical description of the reaction mechanism in equation 1 is so flexible that it allows for a wide range of reaction constants as well as reaction orders. To date neither the reaction constants nor the reaction orders are known for antibody binding reactions. Therefore, we first tested two canonical scenarios for the reaction orders with a wide range of reaction constants to find out which reaction orders lead to realistic predictions for kinetic neutralisation curves. (I) In the first scenario all reaction orders are one, i.e. for . The chemical interpretation of this scenario is that all single step reactions are elementary reactions, we therefore refer to this model as the elementary reaction model. (II) The second scenario tested here reflects the (chemical) stoichiometic parameters of the overall reaction (equation 1), i.e. and for . We therefore refer to this model as the stoichiometric reaction model. In the first scenario, the kinetic neutralisation curves drop very fast and either stays on a constant level or increases again. In Figure 2 we show three typical curves for this model. This behaviour is in contrast to the experimentally observed kinetic neutralisation curves. However, kinetic neutralisation curves of the second scenario can capture the real behaviour (see Figures 3–5 in which the stoichiometric reaction model is used and Figure 5 for data of kinetic neutralisation curves of monoclonal antibodies extracted from [5]). Therefore, we only consider these reaction orders in what follows.


Virus neutralisation: new insights from kinetic neutralisation curves.

Magnus C - PLoS Comput. Biol. (2013)

Predictions for kinetic neutralisation curves for the elementary reaction model.(A) All binding constants are  and all dissociation constants are . The stoichiometry of entry is assumed to be . The starting concentration of antibodies is  and the starting concentration of trimers is . (B) Same constants as in (A) but the starting concentration of antibodies is . (C) The binding constants are  and the dissociation constants are all . The stoichiometry of entry is  and the antibody starting concentration is .
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1002900-g002: Predictions for kinetic neutralisation curves for the elementary reaction model.(A) All binding constants are and all dissociation constants are . The stoichiometry of entry is assumed to be . The starting concentration of antibodies is and the starting concentration of trimers is . (B) Same constants as in (A) but the starting concentration of antibodies is . (C) The binding constants are and the dissociation constants are all . The stoichiometry of entry is and the antibody starting concentration is .
Mentions: The mathematical description of the reaction mechanism in equation 1 is so flexible that it allows for a wide range of reaction constants as well as reaction orders. To date neither the reaction constants nor the reaction orders are known for antibody binding reactions. Therefore, we first tested two canonical scenarios for the reaction orders with a wide range of reaction constants to find out which reaction orders lead to realistic predictions for kinetic neutralisation curves. (I) In the first scenario all reaction orders are one, i.e. for . The chemical interpretation of this scenario is that all single step reactions are elementary reactions, we therefore refer to this model as the elementary reaction model. (II) The second scenario tested here reflects the (chemical) stoichiometic parameters of the overall reaction (equation 1), i.e. and for . We therefore refer to this model as the stoichiometric reaction model. In the first scenario, the kinetic neutralisation curves drop very fast and either stays on a constant level or increases again. In Figure 2 we show three typical curves for this model. This behaviour is in contrast to the experimentally observed kinetic neutralisation curves. However, kinetic neutralisation curves of the second scenario can capture the real behaviour (see Figures 3–5 in which the stoichiometric reaction model is used and Figure 5 for data of kinetic neutralisation curves of monoclonal antibodies extracted from [5]). Therefore, we only consider these reaction orders in what follows.

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