JVI Accepts, published online ahead of print on 4 November 2009

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J. Virol. doi:10.1128/JVI.01535-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Protective memory responses are modulated by priming events prior to challenge

John A. Rutigliano^*, Melissa Y. Morris, Wen Yue, Rachael Keating, Richard J. Webby, Paul G. Thomas, and Peter C. Doherty

Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105

^* To whom correspondence should be addressed. Email: john.rutigliano{at}stjude.org.

Human infections with highly pathogenic H5N1 avian influenza A viruses in the last decade have legitimized fears of a long-predicted pandemic. We thus investigated the response to secondary infections with an engineered, but still highly virulent H5N1 influenza A virus in the C57Bl/6 mouse model. Mice primed with the H1N1 PR8 (A/Puerto Rico/8/34) virus were partially protected from lethality following respiratory infection with this modified H5N1 virus (A/Vietnam/1203/04; Vn1203). In contrast, those that had been comparably exposed to the HKx31 (H3N2) virus succumbed to the Vn1203 challenge, despite similarities in viral replication, weight loss, and secondary CD8+ T cell response characteristics. All three viruses share the internal genes of PR8 that are known to stimulate protective CD8+ T cell-mediated immunity. This differential survival of PR8- and HKx31-primed mice was also apparent for antibody-deficient mice challenged with the Vn1203 virus. The relative protection afforded by PR8 priming was abrogated in TNF^-/- mice, though lung fluids from the B6 HKx31-primed mice contained more TNF early after challenge. These data demonstrate that the nature of the primary infection can influence pathological outcomes following virulent influenza virus challenge, though the effect is not clearly correlated with classical measures of CD8+ T cell-mediated immunity.