3/15/2013

Preemptive priming readily overcomes structure-based mechanisms of virus escape (Proc Natl Acad Sci USA, abstract, edited)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full text: (LINK). Abstract, edited.]

Preemptive priming readily overcomes structure-based mechanisms of virus escape

Sophie A. Valkenburga,1, Stephanie Grasb,1, Carole Guillonneaua,c, Lauren A. Hattona, Nicola A. Birda, Kelly-Anne Twistb, Hanim Halimb, David C. Jacksona, Anthony W. Purcellb, Stephen J. Turnera, Peter C. Dohertya,d,2, Jamie Rossjohnb,e, and Katherine Kedzierskaa,2

Author Affiliations: aDepartment of Microbiology and Immunology, University of Melbourne, Parkville, VIC 3010, Australia; bDepartment of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia; cInstitut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1064, Centre Hospitalier Universitaire Nantes, Centre de Recherche en Transplantation et Immunologie, Faculté de Médecine, Université de Nantes, 44093 Nantes, France; dDepartment of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105-3678; and eInstitute of Infection and Immunity, Cardiff University School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom

Contributed by Peter C. Doherty, February 15, 2013 (sent for review November 25, 2012)

 

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 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.

 

Footnotes

1S.A.V. and S.G. contributed equally to this work.

2To whom correspondence may be addressed. E-mail: pcd@unimelb.edu.au or kkedz@unimelb.edu.au.

Author contributions: S.A.V., S.G., C.G., L.A.H., N.A.B., D.C.J., A.W.P., S.J.T., P.C.D., J.R., and K.K. designed research; S.A.V., S.G., C.G., L.A.H., N.A.B., K.-A.T., H.H., and K.K. performed research; D.C.J. contributed new reagents/analytic tools; S.A.V., S.G., C.G., L.A.H., N.A.B., K.-A.T., H.H., J.R., and K.K. analyzed data; and S.A.V., S.G., A.W.P., S.J.T., P.C.D., J.R., and K.K. wrote the paper.

The authors declare no conflict of interest.

Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.pdb.org [PDB ID codes 4HUU (H2Db-NP-M6I), 4HUV (H2Db-NP-M6W), 4HUW (H2Db-NP-M6T), 4HUX (H2Db-A155-NP), and 4HV8 (H2Db-A155-NP-M6I)].

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1302935110/-/DCSupplemental.

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