Preemptive priming readily overcomes structure-based mechanisms of virus escape

SA Valkenburg; S Gras; C Guillonneau; LA Hatton; NA Bird; KA Twist; H Halim; DC Jackson; AW Purcell; SJ Turner; PC Doherty; J Rossjohn; K Kedzierska

Journal article

Preemptive priming readily overcomes structure-based mechanisms of virus escape

SA Valkenburg, S Gras, C Guillonneau, LA Hatton, NA Bird, KA Twist, H Halim, DC Jackson, AW Purcell, SJ Turner, PC Doherty, J Rossjohn, K Kedzierska

Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2013

DOI: 10.1073/pnas.1302935110

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 DbNP366 epitope. Engineered viruses with a substitution at a critical residue (position 6, P6M) all evaded recognition by WT DbNP366-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 naïve T-cell receptor repertoire, characterized by very limited T-cell receptor diversity and minimal primary respon..

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University of Melbourne Researchers

David Jackson Author

Peter Doherty Author

Jamie Rossjohn Author

Katherine Kedzierska Author

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC) Project Grant

Awarded by National Institutes of Health

Funding Acknowledgements

We thank Dr. Weiguang Zeng for providing the NP-M6T peptide and the staff at the MX beamlines of the Australian synchrotron for assistance with data collection. This work was supported by Australian National Health and Medical Research Council (NHMRC) Project Grant AI1008854 (to K. K.), NHMRC Program Grant APP567122 (to P. C. D., S.J.T., and D.C.J.), and National Institutes of Health Grant AI170251 (to P. C. D.). S. A. V. was a recipient of the Australian Postgraduate Award, K. K. is an NHMRC Career Development Fellow Level 2, A. W. P. is a NHMRC Senior Research Fellow, D.C.J. is an NHMRC Senior Principal Research Fellow, S. G. and S.J.T. are Australian Research Council Future Fellows, and J.R. is an NHMRC Australia Fellow.