Hongwei Ren, Brian J. Ferguson, Carlos Maluquer de Motes, Rebecca P. Sumner, Laura E. R Harman, Geoffrey L. Smith

Factors influencing T-cell responses are important for vaccine development but 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 kappa B (NF-κB) activation. Infection with VACVs that either have the N1L gene deleted (vΔN1) or containing an 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 IFNγ production and greater protection against VACV infection following passive transfer to naïve mice, compared to 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. This article is protected by copyright. All rights reserved.