Dynamics of antibody binding and neutralization during viral infection Público

Abstract

In vivo in infection, virions are constantly produced and die rapidly. In contrast, most antibody binding assays do not include such features. Motivated by this, we considered virions with n = 100 binding sites in simple mathematical models with and without the production of virions. In the absence of viral production, at steady state, the distribution of virions by the number of sites bound is given by a binomial distribution, with the proportion being a simple function of antibody affinity (Kon/Koff) and concentration; this generalizes to a multinomial distribution in the case of two or more kinds of antibodies. In the presence of viral production, the role of affinity is replaced by an infection analog of affinity (IAA), with IAA = Kon/(Koff + dv + r), where dv is the virus decaying rate and r is the infection growth rate. Because in vivo dv can be large, the amount of binding as well as the effect of Koff on binding are substantially reduced. When neutralization is added, the effect of Koff is similarly small which may help explain the relatively high Koff reported for many antibodies. We next show that the n+2 dimensional model used for neutralization can be simplified to a 2 dimensional model. This provides some justification for the simple models that have been used in practice. A corollary of our results is that an unexpectedly large effect of Koff in vivo may point to mechanisms of neutralization beyond stoichiometry. Our results suggest reporting Kon and Koff separately, rather than focusing on affinity, until the situation is better resolved both experimentally and theoretically.

Table of Contents

1. Introduction

2. Results

2.1. Modeling antibody binding

2.1.1. Antibody binding model

2.1.2. Binding at equilibrium scenario (only antibodies-virions interaction)

2.1.3. Binding at non-equilibrium scenario (during viral infection)

2.1.4. Infection analog of affinity

2.2. Modeling antibody neutralization

2.2.1. Change in virus infectivity with the increase in proportion of bound sites

2.2.2. Neutralization models

2.2.3. Simulation results

2.2.4. Effect of Koff

2.3. Simplified antibody neutralization models

3. Discussion

4. References

5. Supplemental Text

5.1. Distribution of the proportion of bound sites

5.1.1 Calculating the steady state of the differential equations describing the binding of multiple types of antibodies:

5.1.2. Analytical solution for proportion of virion bound sites during infection

5.2. The virus infectivity decreases in a convex manner as proportion of bound sites increases

5.2.1 Schematic of the WNV experiment

5.2.2 Justification of relative infection is proportional to relative infectivity

5.3. Alternative curve shapes for the infectivity function

5.4. Hand-drawn lab picture

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Virology Biology, Ecology Biology, Evolution and Development
Palabra Clave	Antibody Antibody Affinity Viral Infection Neutralization
Committee Chair / Thesis Advisor	Rustom Antia, Emory University
Committee Members	Daniel Weissman, Emory University Katia Koelle, Emory University

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