Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells

• Published in: Frontiers in immunology 2019-11, Vol.10, p.2741
• Main Authors: Fisher, Leigh, Zinter, Melissa, Stanfield-Oakley, Sherry, Carpp, Lindsay N, Edwards, R Whitney, Denny, Thomas, Moodie, Zoe, Laher, Fatima, Bekker, Linda-Gail, McElrath, M Juliana, Gilbert, Peter B, Corey, Lawrence, Tomaras, Georgia, Pollara, Justin, Ferrari, Guido
• Format: Article
• Language: English
• Subjects: Adult; AIDS Vaccines - administration & dosage; AIDS Vaccines - immunology; Antibody-Dependent Cell Cytotoxicity; antibody-dependent cellular cytotoxicity; Female; Granzymes - genetics; Granzymes - immunology; HIV Antibodies - immunology; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - prevention & control; HIV Infections - virology; HIV vaccine trial; HIV-1 - genetics; HIV-1 - immunology; HIV-1 infectious molecular clone-infected target cell assay; Humans; Immunology; interleukin-15; Interleukin-15 - immunology; Killer Cells, Natural - immunology; Male; natural killer cells; Young Adult
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.02741

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, 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. , 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.