Adenosine deaminase-1 enhances germinal center formation and functional antibody responses to HIV-1 Envelope DNA and protein vaccines

Ebony Gary, Margaret O'Connor, Marita Chakhtoura, Virginie Tardif, Ogan K. Kumova, Delphine C. Malherbe, William F. Sutton, Nancy L. Haigwood, Michele A. Kutzler, Elias K. Haddad

    Research output: Contribution to journalArticlepeer-review

    2 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)3821-3831
    Number of pages11
    JournalVaccine
    Volume38
    Issue number22
    DOIs
    StatePublished - May 8 2020

    Keywords

    • Adenosine deaminase
    • DNA vaccine
    • HIV
    • Molecular adjuvant

    ASJC Scopus subject areas

    • Molecular Medicine
    • Immunology and Microbiology(all)
    • veterinary(all)
    • Public Health, Environmental and Occupational Health
    • Infectious Diseases

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