Adenosine deaminase-1 enhances germinal center formation and functional antibody responses to HIV-1 Envelope DNA and protein vaccines |
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| Affiliation: | 1. Department of Medicine, Division of Infectious Diseases & HIV Medicine, Drexel University College of Medicine, Philadelphia, PA, United States;2. The Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States;3. The Department of Biochemistry and Cell Biology, Drexel University College of Medicine, Philadelphia, PA, United States;4. Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, United States;1. Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA;2. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA;1. Department of Pediatrics, University of Alberta, AB, Canada;2. Dalla Lana School of Public Health, University of Toronto, ON, Canada;3. Pediatrics and Child Health, Children''s Hospital Research Institute of Manitoba, University of Manitoba, MB, Canada;4. Centre for the Analysis of Genome Evolution and Function, University of Toronto, ON, Canada;5. Department of Medicine, de Groote School of Medicine, McMaster University, ON, Canada;6. Department of Pediatrics, Child & Family Research Institute and BC Children''s Hospital, University of British Columbia, BC, Canada;7. Department of Pediatrics, Hospital for Sick Children, University of Toronto, ON, Canada;8. Agriculture, Food and Nutritional Sciences, University of Alberta, AB, Canada;1. Division of Animal Infectious Diseases, State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China;2. Departments of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA;1. Inovio Pharmaceuticals, Inc., 1787 Sentry Parkway West, Building 18, Suite 400, Blue Bell, PA 19422, USA;2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;3. Special Pathogens Program, National Microbiology Laboratory, Winnipeg, Manitoba R2E 3R2, Canada |
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| Abstract: | Adenosine deaminase-1 (ADA-1) plays both enzymatic and non-enzymatic roles in regulating immune cell function. Mutations in the ADA1 gene account for 15% of heritable severe-combined immunodeficiencies. We determined previously that ADA1 expression defines and is instrumental for the germinal center follicular helper T cell (TFH) phenotype using in vitro human assays. Herein, we tested whether ADA-1 can be used as an adjuvant to improve vaccine efficacy in vivo. In vitro, ADA-1 induced myeloid dendritic cell (mDC) maturation as measured by increased frequencies of CD40-, CD83-, CD86-, and HLA-DR-positive mDCs. ADA-1 treatment also promoted the secretion of the TFH-polarizing cytokine IL-6 from mDCs. In the context of an HIV-1 envelope (env) DNA vaccine, co-immunization with plasmid-encoded ADA-1 (pADA) enhanced humoral immunity. Animals co-immunized with env DNA and pADA had significantly increased frequencies of TFH cells in their draining lymph nodes and increased HIV-binding IgG in serum. Next, mice were co-immunized with subtype C env gp160 DNA and pADA along with simultaneous immunization with matched gp140 trimeric protein. Mice that received env gp160 DNA, pADA, and gp140 glycoprotein had significantly more heterologous HIV-specific binding IgG in their serum. Furthermore, only these mice had detectable neutralizing antibody responses. These studies support the use of ADA-1 as a vaccine adjuvant to qualitatively enhance germinal center responses and represent a novel application of an existing therapeutic agent that can be quickly translated for clinical use. |
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| Keywords: | Adenosine deaminase Molecular adjuvant HIV DNA vaccine |
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