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Enhancement of CD8(+) T-cell memory by removal of a vaccinia virus nuclear factor-κB inhibitor.

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Ren, Hongwei 
Ferguson, Brian J 
Maluquer de Motes, Carlos 
Sumner, Rebecca P 
Harman, Laura ER 


Factors influencing T-cell responses are important for vaccine development but are incompletely understood. Here, vaccinia virus (VACV) protein N1 is shown to impair the development of both effector and memory CD8(+) T cells and this correlates with its inhibition of nuclear factor-κB (NF-κB) activation. Infection with VACVs that either have the N1L gene deleted (vΔN1) or contain a I6E mutation (vN1.I6E) that abrogates its inhibition of NF-κB resulted in increased central and memory CD8(+) T-cell populations, increased CD8(+) T-cell cytotoxicity and lower virus titres after challenge. Furthermore, CD8(+) memory T-cell function was increased following infection with vN1.I6E, with more interferon-γ production and greater protection against VACV infection following passive transfer to naive mice, compared with CD8(+) T cells from mice infected with wild-type virus (vN1.WT). This demonstrates the importance of NF-κB activation within infected cells for long-term CD8(+) T-cell memory and vaccine efficacy. Further, it provides a rationale for deleting N1 from VACV vectors to enhance CD8(+) T-cell immunogenicity, while simultaneously reducing virulence to improve vaccine safety.



CD8+ T-cell memory, N1L gene, nuclear factor-κB inhibitor, vaccination, vaccinia virus, Animals, CD8-Positive T-Lymphocytes, Cell Proliferation, Female, Immunologic Memory, Mice, Mutation, Missense, NF-kappa B, Vaccinia, Vaccinia virus, Viral Proteins, Viral Vaccines

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Medical Research Council (G0900224)
Wellcome Trust (090315/Z/09/Z)
This work was supported by grants from the Wellcome Trust and the Medical Research Council. GLS is a Wellcome Trust Principal Research Fellow.