Gene-modified NK cells expressing CD64 and preloaded with HIV-specific BNAbs target autologous HIV-1-infected CD4+ T cells by ADCC.

IF 3.6 3区 医学 Q2 IMMUNOLOGY Journal of immunology Pub Date : 2025-02-01 DOI:10.1093/jimmun/vkae028
Costin Tomescu, Adiana Ochoa-Ortiz, Lily D Lu, Hong Kong, James L Riley, Luis J Montaner
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Abstract

Natural killer (NK) cells can efficiently mediate antibody-dependent cellular cytotoxicity (ADCC) of antibody coated target cells via the low-affinity Fc-receptor, CD16, but cannot retain antibodies over time. To increase antibody retention and facilitate targeted ADCC, we genetically modified human NK cells with the high-affinity Fc receptor, CD64, so that we could preload them with HIV-specific broadly neutralizing antibodies (BNAbs) and enhance their capacity to target HIV-infected cells via ADCC. Purified NK cells from the peripheral blood of control donors or persons living with HIV were activated with interleukin (IL)-2/IL-15/IL-21 cytokines and transduced with a lentivirus encoding CD64. High levels of CD64 surface expression were maintained for multiple weeks on NK cells and CD64-transduced NK cells were phenotypically similar to control NK cells with strong expression of CD56, CD16, NKG2A, NKp46, CD69, HLA-DR, CD38, and CD57. CD64-transduced NK cells exhibited significantly greater capacity to bind HIV-specific BNAbs in short-term antibody binding assay as well as retain the BNAbs over time (1-wk antibody retention assay) compared with control NK cells only expressing CD16. BNAb-preloaded CD64-transduced NK cells showed a significantly enhanced capacity to mediate ADCC against autologous HIV-1-infected CD4+ primary T cells in both a short-term 4 h degranulation assay as well as a 24 h HIV p24 HIV elimination assay when compared with control NK cells. A chimeric CD64 enhanced NK cell strategy (NuKEs [NK Enhancement Strategy]) retaining bound HIV-specific BNAbs represents a novel autologous primary NK cell immunotherapy strategy against HIV through targeted ADCC.

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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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