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Distinct roles of vaccinia virus NF-kB inhibitor proteins A52, B15 and K7 in the immune response.

Distinct roles of vaccinia virus NF-kB inhibitor proteins A52, B15 and K7 in the immune response.
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Di Pilato M, Mejías-Pérez E, Sorzano COS, Esteban M,


Di Pilato M, Mejías-Pérez E, Sorzano COS, Esteban M, (click to view)

Di Pilato M, Mejías-Pérez E, Sorzano COS, Esteban M,

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Journal of virology 2017 04 19() pii 10.1128/JVI.00575-17

Abstract

Poxviruses use a complex strategy to escape immune control, by expressing immunomodulatory proteins that could limit their use as vaccine vectors. To test the role of poxvirus NF-κB pathway inhibitors A52, B15 and K7 in immunity, we deleted their genes in a NYVAC vaccinia virus strain that expresses HIV-1 clade C antigens. After infection of mice, ablation of A52R, B15R and K7R increased dendritic cell, natural killer cell and neutrophil migration as well as chemokine/cytokine expression. Revertant viruses for these genes confirmed their role in inhibiting the innate immune system. To different extents, enhanced innate immune responses correlated with increased HIV Pol- and Gag-specific polyfunctional CD8 T cell and HIV Env-specific IgG responses induced by single-, double- and triple-deletion mutants. These poxvirus proteins thus influence innate and adaptive cell-mediated and humoral immunity, and their ablation offers alternatives for design of vaccine vectors that regulate immune responses distinctly.IMPORTANCE Poxvirus vectors are used in clinical trials as candidate vaccines for several pathogens, yet how these vectors influence the immune system is unknown. We developed distinct poxvirus vectors that express heterologous antigens but lack different inhibitors of central host-cell signaling pathway. In mice we studied the capacity of these viruses to induce innate and adaptive immune responses and showed that these vectors can distinctly regulate the magnitude and quality of these responses. These findings provide important insights into the mechanism of poxvirus-induced immune response and alternative strategies for vaccine vector design.

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