Academic Journal
Multimeric immunotherapeutic complexes activating natural killer cells towards HIV-1 cure
| العنوان: | Multimeric immunotherapeutic complexes activating natural killer cells towards HIV-1 cure |
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| المؤلفون: | Schober, Rafaëla, Brandus, Bianca, Laeremans, Thessa, Iserentant, Gilles, Rolin, Camille, Dessilly, Géraldine, Zimmer, Jacques, Moutschen, Michel, Aerts, Joeri L, Dervillez, Xavier, Seguin-Devaux, Carole |
| المصدر: | Journal of Translational Medicine, 21 (1), 791 (2023) |
| بيانات النشر: | BioMed Central Ltd, 2023. |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | HIV cure, IL-15, Immunotherapy, KIR2DL, NK cells, NKG2A, Interleukin-15, Humans, Animals, Mice, Interleukin-15/metabolism, CD8-Positive T-Lymphocytes, Quality of Life, Killer Cells, Natural/metabolism, HIV-1, HIV Infections/therapy, Biochemistry, Genetics and Molecular Biology (all), General Biochemistry, Genetics and Molecular Biology, General Medicine, Human health sciences, Immunology & infectious disease, Sciences de la santé humaine, Immunologie & maladie infectieuse |
| الوصف: | [en] BACKGROUND: Combination antiretroviral therapy (cART) has dramatically extended the life expectancy of people living with HIV-1 and improved their quality of life. There is nevertheless no cure for HIV-1 infection since HIV-1 persists in viral reservoirs of latently infected CD4+ T cells. cART does not eradicate HIV-1 reservoirs or restore cytotoxic natural killer (NK) cells which are dramatically reduced by HIV-1 infection, and express the checkpoint inhibitors NKG2A or KIR2DL upregulated after HIV-1 infection. Cytotoxic NK cells expressing the homing receptor CXCR5 were recently described as key subsets controlling viral replication.METHODS: We designed and evaluated the potency of "Natural killer activating Multimeric immunotherapeutic compleXes", called as NaMiX, combining multimers of the IL-15/IL-15Rα complex with an anti-NKG2A or an anti-KIR single-chain fragment variable (scFv) to kill HIV-1 infected CD4+ T cells. The oligomerization domain of the C4 binding protein was used to associate the IL-15/IL-15Rα complex to the scFv of each checkpoint inhibitor as well as to multimerize each entity into a heptamer (α form) or a dimer (β form). Each α or β form was compared in different in vitro models using one-way ANOVA and post-hoc Tukey's tests before evaluation in humanized NSG tg-huIL-15 mice having functional NK cells.RESULTS: All NaMiX significantly enhanced the cytolytic activity of NK and CD8+ T cells against Raji tumour cells and HIV-1+ ACH-2 cells by increasing degranulation, release of granzyme B, perforin and IFN-γ. Targeting NKG2A had a stronger effect than targeting KIR2DL due to higher expression of NKG2A on NK cells. In viral inhibition assays, NaMiX initially increased viral replication of CD4+ T cells which was subsequently inhibited by cytotoxic NK cells. Importantly, anti-NKG2A NaMiX enhanced activation, cytotoxicity, IFN-γ production and CXCR5 expression of NK cells from HIV-1 positive individuals. In humanized NSG tg-huIL-15 mice, we confirmed enhanced activation, degranulation, cytotoxicity of NK cells, and killing of HIV-1 infected cells from mice injected with the anti-NKG2A.α NaMiX, as compared to control mice, as well as decreased total HIV-1 DNA in the lung.CONCLUSIONS: NK cell-mediated killing of HIV-1 infected cells by NaMiX represents a promising approach to support HIV-1 cure strategies. |
| نوع الوثيقة: | journal article http://purl.org/coar/resource_type/c_6501 article peer reviewed |
| اللغة: | English |
| Relation: | https://link.springer.com/content/pdf/10.1186/s12967-023-04669-4.pdf; urn:issn:1479-5876 |
| DOI: | 10.1186/s12967-023-04669-4 |
| URL الوصول: | https://orbi.uliege.be/handle/2268/313068 |
| Rights: | open access http://purl.org/coar/access_right/c_abf2 info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsorb.313068 |
| قاعدة البيانات: | ORBi |
| DOI: | 10.1186/s12967-023-04669-4 |
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