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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

Illustration of the concept of stoichiometries and the parameters used in the model.The sketch in panel (A) depicts a virion with  spikes each consisting of three identical subunits. Thus, each spike has  binding regions for one type of monoclonal antibodies. The virion has  spikes bound to 0 antibodies,  spikes bound to 1 antibody,  and  spikes bound to 2 and 3 antibodies, respectively. Under the assumptions that the stoichiometry of entry is  and the stoichiometry of neutralisation is , the virion is still infectious because it has nine spikes with fewer than two antibodies bound. Panel (B) shows several virions that are neutralised or infectious according to the definition of stoichiometries.
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pcbi-1002900-g001: Illustration of the concept of stoichiometries and the parameters used in the model.The sketch in panel (A) depicts a virion with spikes each consisting of three identical subunits. Thus, each spike has binding regions for one type of monoclonal antibodies. The virion has spikes bound to 0 antibodies, spikes bound to 1 antibody, and spikes bound to 2 and 3 antibodies, respectively. Under the assumptions that the stoichiometry of entry is and the stoichiometry of neutralisation is , the virion is still infectious because it has nine spikes with fewer than two antibodies bound. Panel (B) shows several virions that are neutralised or infectious according to the definition of stoichiometries.

Mentions: As an example, let us consider the virion sketched in Figure 1(A). It has spikes each consisting of subunits (which again is inspired by the structure of an HIV virion). This virion has spikes bound to 0 antibodies, spikes bound to 1 antibody, and spikes bound to 2 and 3 antibodies, respectively. Let us assume that at time point the concentration of spikes bound to one antibody, , equals , and the concentrations , and the concentration of unbound spikes is . The fraction of spikes bound to antibodies is then and . The probability that a virion with spikes has unbound spikes, and five, one, three spikes bound to one, two, three antibodies, respectively, given these concentration is 0.0117 = 1.17%.


Virus neutralisation: new insights from kinetic neutralisation curves.

Magnus C - PLoS Comput. Biol. (2013)

Illustration of the concept of stoichiometries and the parameters used in the model.The sketch in panel (A) depicts a virion with  spikes each consisting of three identical subunits. Thus, each spike has  binding regions for one type of monoclonal antibodies. The virion has  spikes bound to 0 antibodies,  spikes bound to 1 antibody,  and  spikes bound to 2 and 3 antibodies, respectively. Under the assumptions that the stoichiometry of entry is  and the stoichiometry of neutralisation is , the virion is still infectious because it has nine spikes with fewer than two antibodies bound. Panel (B) shows several virions that are neutralised or infectious according to the definition of stoichiometries.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1002900-g001: Illustration of the concept of stoichiometries and the parameters used in the model.The sketch in panel (A) depicts a virion with spikes each consisting of three identical subunits. Thus, each spike has binding regions for one type of monoclonal antibodies. The virion has spikes bound to 0 antibodies, spikes bound to 1 antibody, and spikes bound to 2 and 3 antibodies, respectively. Under the assumptions that the stoichiometry of entry is and the stoichiometry of neutralisation is , the virion is still infectious because it has nine spikes with fewer than two antibodies bound. Panel (B) shows several virions that are neutralised or infectious according to the definition of stoichiometries.
Mentions: As an example, let us consider the virion sketched in Figure 1(A). It has spikes each consisting of subunits (which again is inspired by the structure of an HIV virion). This virion has spikes bound to 0 antibodies, spikes bound to 1 antibody, and spikes bound to 2 and 3 antibodies, respectively. Let us assume that at time point the concentration of spikes bound to one antibody, , equals , and the concentrations , and the concentration of unbound spikes is . The fraction of spikes bound to antibodies is then and . The probability that a virion with spikes has unbound spikes, and five, one, three spikes bound to one, two, three antibodies, respectively, given these concentration is 0.0117 = 1.17%.

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