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

Article scientifique 2019 Anglais

Résumé

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 NK cells improved the ability of the vaccine-induced antibodies to recruit NK cells for ADCC. Through immunophenotyping experiments, we showed that this improved killing was likely due to IL-15 mediated activation of the NK cells and higher intracellular levels of perforin and granzyme B in the IL-15 pretreated 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.

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Fisher, L., Zinter, M., Stanfield-Oakley, S., Carpp, L., Edwards, R., Denny, T., Moodie, Z., Laher, F., Bekker, L., McElrath, M., Gilbert, P., Corey, L., Tomaras, G., Pollara, J., Ferrari, G. (2019). Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells. https://doi.org/10.3389/fimmu.2019.02741

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Auteur(s)

Leigh H. Fisher Melissa Zinter Sherry Stanfield-Oakley Lindsay N. Carpp R. Whitney Edwards Thomas N. Denny Zoe Moodie Fatima Laher Linda‐Gail Bekker M. Juliana McElrath Peter B. Gilbert Lawrence Corey Georgia D. Tomaras Justin Pollara Guido Ferrari

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