Preemptive priming readily overcomes structure-based mechanisms of virus escape

Sophie A Valkenburg, Stephanie Gras, Carole Guillonneau, Lauren A Hatten, Nicola L Bird, Kelly-Anne Twist, Noor Hanim Abd Halim, David C Jackson, Anthony Wayne Purcell, Stephen J Turner, Peter C Doherty, Jamie Rossjohn, Katherine Kedzierska

Research output: Contribution to journalArticleResearchpeer-review

Abstract

A reverse-genetics approach has been used to probe the mechanism underlying immune escape for influenza A virus-specific CD8(+) T cells responding to the immunodominant D(b)NP366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT D(b)NP366-specific CD8(+) T cells, but only the NPM6I and NPM6T mutants altered the topography of a key residue (His155) in the MHC class I binding site. Following infection with the engineered NPM6I and NPM6T influenza viruses, both mutations were associated with a substantial hole in the naive T-cell receptor repertoire, characterized by very limited T-cell receptor diversity and minimal primary responses to the NPM6I and NPM6T epitopes. Surprisingly, following respiratory challenge with a serologically distinct influenza virus carrying the same mutation, preemptive immunization against these escape variants led to the generation of secondary CD8(+) T-cell responses that were comparable in magnitude to those found for the WT NP epitope. Consequently, it might be possible to generate broadly protective T-cell immunity against commonly occurring virus escape mutants. If this is generally true for RNA viruses (like HIV, hepatitis C virus, and influenza) that show high mutation rates, priming against predicted mutants before an initial encounter could function to prevent the emergence of escape variants in infected hosts. That process could be a step toward preserving immune control of particularly persistent RNA viruses and may be worth considering for future vaccine strategies.
Original languageEnglish
Pages (from-to)5570 - 5575
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume110
Issue number14
DOIs
Publication statusPublished - 2013

Cite this

Valkenburg, S. A., Gras, S., Guillonneau, C., Hatten, L. A., Bird, N. L., Twist, K-A., ... Kedzierska, K. (2013). Preemptive priming readily overcomes structure-based mechanisms of virus escape. Proceedings of the National Academy of Sciences, 110(14), 5570 - 5575. https://doi.org/10.1073/pnas.1302935110
Valkenburg, Sophie A ; Gras, Stephanie ; Guillonneau, Carole ; Hatten, Lauren A ; Bird, Nicola L ; Twist, Kelly-Anne ; Abd Halim, Noor Hanim ; Jackson, David C ; Purcell, Anthony Wayne ; Turner, Stephen J ; Doherty, Peter C ; Rossjohn, Jamie ; Kedzierska, Katherine. / Preemptive priming readily overcomes structure-based mechanisms of virus escape. In: Proceedings of the National Academy of Sciences. 2013 ; Vol. 110, No. 14. pp. 5570 - 5575.
@article{0888b32538f1455bb50ebf8489d7ce17,
title = "Preemptive priming readily overcomes structure-based mechanisms of virus escape",
abstract = "A reverse-genetics approach has been used to probe the mechanism underlying immune escape for influenza A virus-specific CD8(+) T cells responding to the immunodominant D(b)NP366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT D(b)NP366-specific CD8(+) T cells, but only the NPM6I and NPM6T mutants altered the topography of a key residue (His155) in the MHC class I binding site. Following infection with the engineered NPM6I and NPM6T influenza viruses, both mutations were associated with a substantial hole in the naive T-cell receptor repertoire, characterized by very limited T-cell receptor diversity and minimal primary responses to the NPM6I and NPM6T epitopes. Surprisingly, following respiratory challenge with a serologically distinct influenza virus carrying the same mutation, preemptive immunization against these escape variants led to the generation of secondary CD8(+) T-cell responses that were comparable in magnitude to those found for the WT NP epitope. Consequently, it might be possible to generate broadly protective T-cell immunity against commonly occurring virus escape mutants. If this is generally true for RNA viruses (like HIV, hepatitis C virus, and influenza) that show high mutation rates, priming against predicted mutants before an initial encounter could function to prevent the emergence of escape variants in infected hosts. That process could be a step toward preserving immune control of particularly persistent RNA viruses and may be worth considering for future vaccine strategies.",
author = "Valkenburg, {Sophie A} and Stephanie Gras and Carole Guillonneau and Hatten, {Lauren A} and Bird, {Nicola L} and Kelly-Anne Twist and {Abd Halim}, {Noor Hanim} and Jackson, {David C} and Purcell, {Anthony Wayne} and Turner, {Stephen J} and Doherty, {Peter C} and Jamie Rossjohn and Katherine Kedzierska",
year = "2013",
doi = "10.1073/pnas.1302935110",
language = "English",
volume = "110",
pages = "5570 -- 5575",
journal = "Proceedings of the National Academy of Sciences",
issn = "0027-8424",
publisher = "National Acad Sciences",
number = "14",

}

Valkenburg, SA, Gras, S, Guillonneau, C, Hatten, LA, Bird, NL, Twist, K-A, Abd Halim, NH, Jackson, DC, Purcell, AW, Turner, SJ, Doherty, PC, Rossjohn, J & Kedzierska, K 2013, 'Preemptive priming readily overcomes structure-based mechanisms of virus escape' Proceedings of the National Academy of Sciences, vol. 110, no. 14, pp. 5570 - 5575. https://doi.org/10.1073/pnas.1302935110

Preemptive priming readily overcomes structure-based mechanisms of virus escape. / Valkenburg, Sophie A; Gras, Stephanie; Guillonneau, Carole; Hatten, Lauren A; Bird, Nicola L; Twist, Kelly-Anne; Abd Halim, Noor Hanim; Jackson, David C; Purcell, Anthony Wayne; Turner, Stephen J; Doherty, Peter C; Rossjohn, Jamie; Kedzierska, Katherine.

In: Proceedings of the National Academy of Sciences, Vol. 110, No. 14, 2013, p. 5570 - 5575.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Preemptive priming readily overcomes structure-based mechanisms of virus escape

AU - Valkenburg, Sophie A

AU - Gras, Stephanie

AU - Guillonneau, Carole

AU - Hatten, Lauren A

AU - Bird, Nicola L

AU - Twist, Kelly-Anne

AU - Abd Halim, Noor Hanim

AU - Jackson, David C

AU - Purcell, Anthony Wayne

AU - Turner, Stephen J

AU - Doherty, Peter C

AU - Rossjohn, Jamie

AU - Kedzierska, Katherine

PY - 2013

Y1 - 2013

N2 - A reverse-genetics approach has been used to probe the mechanism underlying immune escape for influenza A virus-specific CD8(+) T cells responding to the immunodominant D(b)NP366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT D(b)NP366-specific CD8(+) T cells, but only the NPM6I and NPM6T mutants altered the topography of a key residue (His155) in the MHC class I binding site. Following infection with the engineered NPM6I and NPM6T influenza viruses, both mutations were associated with a substantial hole in the naive T-cell receptor repertoire, characterized by very limited T-cell receptor diversity and minimal primary responses to the NPM6I and NPM6T epitopes. Surprisingly, following respiratory challenge with a serologically distinct influenza virus carrying the same mutation, preemptive immunization against these escape variants led to the generation of secondary CD8(+) T-cell responses that were comparable in magnitude to those found for the WT NP epitope. Consequently, it might be possible to generate broadly protective T-cell immunity against commonly occurring virus escape mutants. If this is generally true for RNA viruses (like HIV, hepatitis C virus, and influenza) that show high mutation rates, priming against predicted mutants before an initial encounter could function to prevent the emergence of escape variants in infected hosts. That process could be a step toward preserving immune control of particularly persistent RNA viruses and may be worth considering for future vaccine strategies.

AB - A reverse-genetics approach has been used to probe the mechanism underlying immune escape for influenza A virus-specific CD8(+) T cells responding to the immunodominant D(b)NP366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT D(b)NP366-specific CD8(+) T cells, but only the NPM6I and NPM6T mutants altered the topography of a key residue (His155) in the MHC class I binding site. Following infection with the engineered NPM6I and NPM6T influenza viruses, both mutations were associated with a substantial hole in the naive T-cell receptor repertoire, characterized by very limited T-cell receptor diversity and minimal primary responses to the NPM6I and NPM6T epitopes. Surprisingly, following respiratory challenge with a serologically distinct influenza virus carrying the same mutation, preemptive immunization against these escape variants led to the generation of secondary CD8(+) T-cell responses that were comparable in magnitude to those found for the WT NP epitope. Consequently, it might be possible to generate broadly protective T-cell immunity against commonly occurring virus escape mutants. If this is generally true for RNA viruses (like HIV, hepatitis C virus, and influenza) that show high mutation rates, priming against predicted mutants before an initial encounter could function to prevent the emergence of escape variants in infected hosts. That process could be a step toward preserving immune control of particularly persistent RNA viruses and may be worth considering for future vaccine strategies.

UR - http://www.pnas.org/content/110/14/5570.full.pdf

U2 - 10.1073/pnas.1302935110

DO - 10.1073/pnas.1302935110

M3 - Article

VL - 110

SP - 5570

EP - 5575

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 0027-8424

IS - 14

ER -