期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：11
页码：E1333-E1342
DOI：10.1073/pnas.1424341112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAlthough poxvirus vectors are widely used in preclinical and clinical trials as candidate vaccines for multiple pathogens, how these vectors affect the host immune response is not clear. In this study, we developed a poxvirus vector based on the attenuated New York vaccinia virus (NYVAC), which is able to target a central host-cell signaling pathway, NF{kappa}B. In mice, the modified NYVAC acts on the immune system by increasing specific neutrophil migration via NF{kappa}B activation and in turn enhances CD8 T-cell responses to HIV antigens delivered by the viral vector. We show that these inherent properties define a mechanism for poxvirus-induced immune responses and offer novel approaches to vaccine vector design. Neutrophils are antigen-transporting cells that generate vaccinia virus (VACV)-specific T-cell responses, yet how VACV modulates neutrophil recruitment and its significance in the immune response are unknown. We generated an attenuated VACV strain that expresses HIV-1 clade C antigens but lacks three specific viral genes (A52R, K7R, and B15R). We found that these genes act together to inhibit the NF{kappa}B signaling pathway. Triple ablation in modified virus restored NF{kappa}B function in macrophages. After virus infection of mice, NF{kappa}B pathway activation led to expression of several cytokines/chemokines that increased the migration of neutrophil populations (N and N{beta}) to the infection site. N{beta} cells displayed features of antigen-presenting cells and activated virus-specific CD8 T cells. Enhanced neutrophil trafficking to the infection site correlated with an increased T-cell response to HIV vector-delivered antigens. These results identify a mechanism for poxvirus-induced immune response and alternatives for vaccine vector design.
关键词：vaccinia virus ; neutrophils ; NFκB ; vaccine ; HIV
