title: Transgenic 4-1BBL-engineered vaccine stimulates potent Gag-specific therapeutic and long-term immunity via increased priming of CD44(+)CD62L(high) IL-7R(+) CTLs with up- and downregulation of anti- and pro-apoptosis genes.
abstract: Human immunodeficiency virus type-1 (HIV-1)-specific dendritic cell (DC) vaccines have been used in clinical trials. However, they have been found to only induce some degree of immune responses in these studies. We previously demonstrated that the HIV-1 Gag-specific Gag-Texo vaccine stimulated Gag-specific effector CD8(+) cytotoxic T lymphocyte (CTL) responses, leading to completely protective, but very limited, therapeutic immunity. In this study, we constructed a recombinant adenoviral vector, adenovirus (AdV)4-1BBL, which expressed mouse 4-1BB ligand (4-1BBL), and generated transgenic 4-1BBL-engineered OVA-Texo/4-1BBL and Gag-Texo/4-1BBL vaccines by transfecting ovalbumin (OVA)-Texo and Gag-Texo cells with AdV4-1BBL, respectively. We demonstrate that the OVA-specific OVA-Texo/4-1BBL vaccine stimulates more efficient OVA-specific CTL responses (3.26%) compared to OVA-Texo-activated responses (1.98%) in wild-type C57BL/6 mice and the control OVA-Texo/Null vaccine without transgenic 4-1BBL expression, leading to enhanced therapeutic immunity against 6-day established OVA-expressing B16 melanoma BL6-10OVA cells. OVA-Texo/4-1BBL-stimulated CTLs, which have a CD44(+)CD62L(high) IL-7R(+) phenotype, are likely memory CTL precursors, demonstrating prolonged survival and enhanced differentiation into memory CTLs with functional recall responses and long-term immunity against BL6-10OVA melanoma. In addition, we demonstrate that OVA-Texo/4-1BBL-stimulated CTLs up- and downregulate the expression of anti-apoptosis (Bcl2l10, Naip1, Nol3, Pak7 and Tnfrsf11b) and pro-apoptosis (Casp12, Trp63 and Trp73) genes, respectively, by RT(2) Profiler PCR array analysis. Importantly, the Gag-specific Gag-Texo/4-1BBL vaccine also stimulates more efficient Gag-specific therapeutic and long-term immunity against HLA-A2/Gag-expressing B16 melanoma BL6-10Gag/A2 cells than the control Gag-Texo/Null vaccine in transgenic HLA-A2 mice. Taken together, our novel Gag-Texo/4-1BBL vaccine, which is capable of stimulating potent Gag-specific therapeutic and long-term immunity, may represent a new immunotherapeutic vaccine for controlling HIV-1 infection.
authors.affiliation: 1] Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada [2] Department of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Freywald
authors.affiliation: Department of Epidemiology and Community Health, University of Ottawa, Canada.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
authors.affiliation: School of Life Science, Beijing Institute of Technology, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tan
authors.affiliation: 1] Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada [2] Department of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology*; D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory; D019041:L-Selectin / Q000235:genetics / Q000276:immunology; D051379:Mice; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D053330:4-1BB Ligand; D016915:AIDS Vaccines; D019496:Cancer Vaccines; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D020395:Receptors, Interleukin-7; D019041:L-Selectin