Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells.
Abstract
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.
Type
Journal articleSubject
Killer Cells, NaturalHumans
HIV-1
HIV Infections
Interleukin-15
AIDS Vaccines
HIV Antibodies
Antibody-Dependent Cell Cytotoxicity
Adult
Female
Male
Granzymes
Young Adult
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https://hdl.handle.net/10161/21998Published Version (Please cite this version)
10.3389/fimmu.2019.02741Publication Info
Fisher, 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Thomas Norton Denny
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
Guido Ferrari
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
Justin Joseph Pollara
Associate Professor in Surgery
Georgia Doris Tomaras
Professor in Surgery
Dr. Georgia Tomaras is a tenured Professor of Surgery, Professor of Immunology, Professor
of Molecular Genetics and Microbiology and is a Fellow of the American Academy of
Microbiology (AAM) and a Fellow of the American Association for the Advancement of
Science (AAAS). Dr. Tomaras is Co-Director of the Center for Human Systems Immunology
(CHSI) Duke University and Director of the Duke Center for AIDS Research (CFAR). Her
national and international leadership roles i
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