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
Abstract :
[en] [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.
Disciplines :
Immunology & infectious disease
Author, co-author :
Schober, Rafaëla; Department of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354, Esch-Sur-Alzette, Luxembourg
Brandus, Bianca; Department of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354, Esch-Sur-Alzette, Luxembourg
Laeremans, Thessa; Neuro-Aging and Viro-Immunotherapy (NAVI) Research Group, Faculty of Pharmacy and Medicine, Vrije Universiteit Brussel, 1090, Brussels, Belgium
Iserentant, Gilles; Department of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354, Esch-Sur-Alzette, Luxembourg
Rolin, Camille; Department of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354, Esch-Sur-Alzette, Luxembourg
Dessilly, Géraldine; AIDS Reference Laboratory, Catholic University of Louvain, Ottignies-Louvain-la-Neuve, Belgium
Zimmer, Jacques; Department of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354, Esch-Sur-Alzette, Luxembourg
Moutschen, Michel ; Centre Hospitalier Universitaire de Liège - CHU > > Service des maladies infectieuses - médecine interne
Aerts, Joeri L; Neuro-Aging and Viro-Immunotherapy (NAVI) Research Group, Faculty of Pharmacy and Medicine, Vrije Universiteit Brussel, 1090, Brussels, Belgium
Dervillez, Xavier; Department of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354, Esch-Sur-Alzette, Luxembourg
Seguin-Devaux, Carole ; Department of Infection and Immunity, Luxembourg Institute of Health, 29, Rue Henri Koch, L-4354, Esch-Sur-Alzette, Luxembourg. carole.devaux@lih.lu
Language :
English
Title :
Multimeric immunotherapeutic complexes activating natural killer cells towards HIV-1 cure
FNR - Fonds National de la Recherche MESR - Ministère de l'Enseignement Supérieur et de la Recherche
Funding text :
This study was supported by the “Fonds National de la Recherche” (PRIDE/11012546/Next Immune-DTU and PRIDE17/11823097/MICROH-DTU) and the Ministry of Higher Education and Research of Luxembourg (LIH GBB 98000005).The following reagents were obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: ACH-2 Cells, ARP-349, contributed by Dr. Thomas Folks; Human Immunodeficiency Virus Type 1 IIIB Tat Protein, Recombinant from Escherichia coli, ARP-2222, contributed by DAIDS/NIAID; produced by ABL, Inc; Human Immunodeficiency Virus 1 (HIV-1), Strain JR-CSF Infectious Molecular Clone (pYK-JRCSF), ARP-2708, contributed by Dr. Irvin S. Y. Chen and Dr. Yoshio Koyanagi. The HLA-E expressing K562 cells were a kind gift from prof. Thorbald van Hall, University of Leiden.
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