Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells.
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The secondary analyses for correlates of risk of infection in the RV144 HIV-1 vaccine trial implicated vaccine-induced antibody-dependent cellular cytotoxicity (ADCC) responses in the observed protection, highlighting the importance of assessing such responses in ongoing and future HIV-1 vaccine trials. However, in vitro assays that detect ADCC activity in plasma from HIV-1 infected seropositive individuals are not always effective at detecting ADCC activity in plasma from HIV-1 vaccine recipients. In vivo, ADCC-mediating antibodies must operate at the site of infection, where effector cells are recruited and activated by a local milieu of chemokines and cytokines. Based on previous findings that interleukin 15 (IL-15) secretion increases during acute HIV-1 infection and enhances NK cell-mediated cytotoxicity, we hypothesized that IL-15 pretreatment of NK effector cells could be used to improve killing of infected cells by vaccine-induced antibodies capable of mediating ADCC. Using the HIV-1 infectious molecular clone (IMC)-infected target cell assay along with plasma samples from HIV-1 vaccine recipients, we found that IL-15 treatment of effector cells improved the ability of the vaccine-induced antibodies to recruit effector cells for ADCC. Through immunophenotyping experiments, we showed that this improved killing was likely due to IL-15 mediated activation of NK effector cells and higher intracellular levels of perforin and granzyme B in the IL-15 pretreated NK cells. We also found that using a 4-fold dilution series of plasma and subtraction of pre-vaccination responses resulted in lowest response rates among placebo recipients and significant separation between treatment groups. This represents the first attempt to utilize IL-15-treated effector cells and optimized analytical approaches to improve the detection of HIV-1 vaccine-induced ADCC responses and will inform analyses of future HIV vaccine clinical trials.
SubjectKiller Cells, Natural
Antibody-Dependent Cell Cytotoxicity
Published Version (Please cite this version)10.3389/fimmu.2019.02741
Publication InfoFisher, Leigh; Zinter, Melissa; Stanfield-Oakley, Sherry; Carpp, Lindsay N; Edwards, R Whitney; Denny, Thomas; ... Ferrari, Guido (2019). Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells. Frontiers in immunology, 10. pp. 2741. 10.3389/fimmu.2019.02741. Retrieved from https://hdl.handle.net/10161/21998.
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Professor in Medicine
Thomas N. Denny, MSc, M.Phil, is the Chief Operating Officer of the Duke Human Vaccine Institute (DHVI) and the Center for HIV/AIDS Vaccine Immunology (CHAVI), and a Professor of Medicine in the Department of Medicine at Duke University Medical Center. He is also an Affiliate Member of the Duke Global Health Institute. He has recently been appointed to the Duke University Fuqua School of Business Health Sector Advisory Council. Previously, he was an Associate Professor of Pathology, Laboratory M
Professor in Surgery
The activities of the Ferrari Laboratory are based on both independent basic research and immune monitoring studies. The research revolves around three main areas of interest: class I-mediated cytotoxic CD8+ T cell responses, antibody-dependent cellular cytotoxicity (ADCC), gene expression in NK and T cellular subsets upon infection with HIV-1. With continuous funding over the last 11 years from the NIH and Bill & Melinda Gates Foundation along with many other productive collaborations wi
Associate Professor in Surgery
Professor in Surgery
Research in the Tomaras Laboratory in the Duke Human Vaccine Institute and Departments of Surgery, Immunology, and Molecular Genetics and Microbiology at Duke University Medical Center, focuses on the identification of immune correlates of protection for preventative vaccines and identification of the mechanisms responsible for potent inhibition of human pathogens.
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