Evolution of CD8 T Cell Epitopes of Influenza A Virus Public

Abstract

Influenza-specific CD8 T cells protect against severe pathology caused by heterosubtypic infection, mainly due to the conservation of influenza CD8 T cell epitopes. This conservation may be explained by (1) functional constraints, (2) small selection on the escaping mutant, and (3) human MHC polymorphism. We aim to model the interplay of these factors and quantify the parameters experimentally.

We constructed a population genetics model that incorporates fitness cost, selective advantage, and MHC allele frequency. Additionally, the development of compensatory immunity was considered by an ordinary differential equation system. Guided by the model, we designed a series of experiments to estimate the parameters. We introduced an escaping mutation to the nucleoprotein (NP) under PR8 (H1N1) back-ground. C57BL/6 mice of different immune status were challenged with a 1:1 mixture of wild-type and mutant PR8 and the lung viral load of each strain was measured by digital droplet PCR.

The population genetics model predicts that, within biologically reasonable range of parameters, it takes 3 to 10 years for an CD8 T cell-escaping mutant to reach 50% of prevalence in the population, if it does. The development of compensatory immunity further renders the invasion ‘transiently’ when the compensation level is beyond a threshold determined by above-mentioned parameters. Based on the area under in vivo viral growth curves, the selective advantage of the mutant PR8 is 0.27 [0.08, 0.2] in the intranasally primed C57BL/6 mice. Interestingly, the selective advantage significantly reduced in the intramuscularly primed C57BL/6 mice (0.04 [0.02, 0.06]).

We concluded that a CD8 T cell-escaping mutant either cannot invade or invades extremely slowly, if the invasion entirely depends on selection. The lower selective ad-vantage in intramuscularly primed mice suggests the lung-resident memory CD8 T cells may be the primary source of selection pressure on influenza virus.

Table of Contents

1 Introduction

1.1 Influenza A Virus

1.2 Immune Responses to IAV Infection

1.3 Evolution of IAV

1.4 Concluding Remarks

2 Modeling the Invasion of a CD8 T Cell-escaping IAV Variant

2.1 Results

2.2 Materials and Methods

2.3 Appendix

3 Quantifying the Memory CD8 T Cell-mediated Immune Selection Pressure on Influenza A Virus In Vivo

3.1 Results

3.2 Materials and Methods

3.3 Appendix

4 Discussion

4.1 Scientific Questions

4.2 Discussion of the Results

4.3 Framework of Measuring Viral Fitness

4.4 Implications on T Cell-based Vaccines

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Immunology and Molecular Pathogenesis
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Virology Biology, Evolution and Development
Mot-clé	Selection Influenza A virus T cell immunity
Committee Chair / Thesis Advisor	Rustom Antia, Emory University Jacob E. Kohlmeier, Emory University
Committee Members	Lance A. Waller, Emory University Anice C. Lowen, Emory University John D. Altman, Emory University

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