NFκB activation by modified vaccinia virus as a novel strategy to enhance neutrophil migration and HIV-specific T-cell responses.
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 NFκB signaling pathway. Triple ablation in modified virus restored NFκB function in macrophages. After virus infection of mice, NFκB pathway activation led to expression of several cytokines/chemokines that increased the migration of neutrophil populations (Nα and Nβ) to the infection site. Nβ 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.
Departments of Molecular and Cellular Biology and.
Mauro
M
Di Pilato
Departments of Molecular and Cellular Biology and.
Ernesto
E
Mejías-Pérez
Immunology and Oncology and.
Manuela
M
Zonca
Departments of Molecular and Cellular Biology and.
Beatriz
B
Perdiguero
Departments of Molecular and Cellular Biology and.
Carmen Elena
CE
Gómez
Cell Division and Cancer Group, Spanish National Cancer Research Centre, Madrid 28029, Spain;
Marianna
M
Trakala
Departments of Molecular and Cellular Biology and.
Jacobo
J
Nieto
Departments of Molecular and Cellular Biology and.
José Luis
JL
Nájera
Biocomputing Unit, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, Madrid 28049, Spain;
Carlos Oscar S
CO
Sorzano
INSERM UMR_S 945, Faculté de Médecine Pitié-Salpétrière, Laboratoire Immunité et Infection, Paris 75013, France; and.
Christophe
C
Combadière
Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne 1011, Switzerland.
Giuseppe
G
Pantaleo
Immunology and Oncology and.
Lourdes
L
Planelles
Departments of Molecular and Cellular Biology and mesteban@cnb.csic.es.
Mariano
M
Esteban
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D017353:Gene Deletion; D005814:Genes, Viral; D015488:HIV Antigens / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007154:Immune System Diseases; D007960:Leukocyte Disorders; D008213:Lymphocyte Activation / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D020556:Neutrophil Infiltration; D013045:Species Specificity; D014615:Vaccinia / Q000276:immunology / Q000821:virology; D014616:Vaccinia virus / Q000235:genetics
D015488:HIV Antigens; D016328:NF-kappa B
HIV; NFκB; neutrophils; vaccine; vaccinia virus