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 [LU] MESR - Ministère de l'Enseignement Supérieur et de la Recherche [LU]
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.
Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003;9(6):727–8.
Dubé K, Willenberg L, Dee L, Sylla L, Taylor J, Roebuck C, et al. Re-examining the HIV ‘functional cure’ oxymoron: time for precise terminology? J Virus Erad. 2020;6(4):100017.
Garrido C, Abad-Fernandez M, Tuyishime M, Pollara JJ, Ferrari G, Soriano-Sarabia N, et al. Interleukin-15-stimulated natural killer cells clear HIV-1-infected cells following latency reversal ex vivo. J Virol. 2018;92(12):10–1128.
Bernard NF, Kant S, Kiani Z, Tremblay C, Dupuy FP. Natural killer cells in antibody independent and antibody dependent HIV control. Front Immunol. 2022;13:879124.
Alter G, Teigen N, Ahern R, Streeck H, Meier A, Rosenberg ES, et al. Evolution of innate and adaptive effector cell functions during acute HIV-1 infection. J Infect Dis. 2007;195(10):1452–60.
Alter G, Teigen N, Davis BT, Addo MM, Suscovich TJ, Waring MT, et al. Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection. Blood. 2005;106(10):3366–9.
Mavilio D, Lombardo G, Benjamin J, Kim D, Follman D, Marcenaro E, et al. Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci U S A. 2005;102(8):2886–91.
De Maria A, Fogli M, Costa P, Murdaca G, Puppo F, Mavilio D, et al. The impaired NK cell cytolytic function in viremic HIV-1 infection is associated with a reduced surface expression of natural cytotoxicity receptors (NKp46, NKp30 and NKp44). Eur J Immunol. 2003;33(9):2410–8.
Azzoni L, Papasavvas E, Chehimi J, Kostman JR, Mounzer K, Ondercin J, et al. Sustained impairment of IFN-gamma secretion in suppressed HIV-infected patients despite mature NK cell recovery: evidence for a defective reconstitution of innate immunity. J Immunol. 2002;168(11):5764–70.
Frias M, Rivero-Juarez A, Gordon A, Camacho A, Cantisan S, Cuenca-Lopez F, et al. Persistence of pathological distribution of NK cells in HIV-infected patients with prolonged use of HAART and a sustained immune response. PLoS ONE. 2015;10(3):e0121019.
Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, et al. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012;36(3):491–501.
Guo AL, Jiao YM, Zhao QW, Huang HH, Deng JN, Zhang C, et al. Implications of the accumulation of CXCR5(+) NK cells in lymph nodes of HIV-1 infected patients. EBioMedicine. 2022;75:103794.
Mueller YM, Petrovas C, Bojczuk PM, Dimitriou ID, Beer B, Silvera P, et al. Interleukin-15 increases effector memory CD8+ t cells and NK cells in simian immunodeficiency virus-infected macaques. J Virol. 2005;79(8):4877–85.
Ranson T, Vosshenrich CA, Corcuff E, Richard O, Müller W, Di Santo JP. IL-15 is an essential mediator of peripheral NK-cell homeostasis. Blood. 2003;101(12):4887–93.
Fantini M, David JM, Wong HC, Annunziata CM, Arlen PM, Tsang KY. An IL-15 superagonist, ALT-803, enhances antibody-dependent cell-mediated cytotoxicity elicited by the monoclonal antibody NEO-201 against human carcinoma cells. Cancer Biother Radiopharm. 2019;34(3):147–59.
Liu B, Kong L, Han K, Hong H, Marcus WD, Chen X, et al. A novel fusion of ALT-803 (interleukin (IL)-15 superagonist) with an antibody demonstrates antigen-specific antitumor responses. J Biol Chem. 2016;291(46):23869–81.
Kim PS, Kwilas AR, Xu W, Alter S, Jeng EK, Wong HC, et al. IL-15 superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas. Oncotarget. 2016;7(13):16130–45.
Xu W, Jones M, Liu B, Zhu X, Johnson CB, Edwards AC, et al. Efficacy and mechanism-of-action of a novel superagonist interleukin-15: interleukin-15 receptor alphaSu/Fc fusion complex in syngeneic murine models of multiple myeloma. Cancer Res. 2013;73(10):3075–86.
Dubois S, Mariner J, Waldmann TA, Tagaya Y. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity. 2002;17(5):537–47.
Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clin Oncol. 2015;33(1):74–82.
Chertova E, Bergamaschi C, Chertov O, Sowder R, Bear J, Roser JD, et al. Characterization and favorable in vivo properties of heterodimeric soluble IL-15·IL-15Rα cytokine compared to IL-15 monomer. J Biol Chem. 2013;288(25):18093–103.
Bergamaschi C, Watson DC, Valentin A, Bear J, Peer CJ, Figg WD Sr, et al. Optimized administration of hetIL-15 expands lymphocytes and minimizes toxicity in rhesus macaques. Cytokine. 2018;108:213–24.
Ellis-Connell AL, Balgeman AJ, Zarbock KR, Barry G, Weiler A, Egan JO, et al. ALT-803 transiently reduces simian immunodeficiency virus replication in the absence of antiretroviral treatment. J Virol. 2018. 10.1128/JVI.01748-17. DOI: 10.1128/JVI.01748-17
Watson DC, Moysi E, Valentin A, Bergamaschi C, Devasundaram S, Fortis SP, et al. Treatment with native heterodimeric IL-15 increases cytotoxic lymphocytes and reduces SHIV RNA in lymph nodes. PLoS Pathog. 2018;14(2):e1006902.
Webb GM, Li S, Mwakalundwa G, Folkvord JM, Greene JM, Reed JS, et al. The human IL-15 superagonist ALT-803 directs SIV-specific CD8(+) T cells into B-cell follicles. Blood Adv. 2018;2(2):76–84.
Jones RB, Mueller S, O’Connor R, Rimpel K, Sloan DD, Karel D, et al. A Subset of latency-reversing agents expose HIV-infected resting CD4+ T-cells to recognition by cytotoxic T-lymphocytes. PLoS Pathog. 2016;12(4):e1005545.
Webb GM, Molden J, Busman-Sahay K, Abdulhaqq S, Wu HL, Weber WC, et al. The human IL-15 superagonist N-803 promotes migration of virus-specific CD8+ T and NK cells to B cell follicles but does not reverse latency in ART-suppressed, SHIV-infected macaques. PLoS Pathog. 2020;16(3):e1008339.
Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56.
Levy EM, Bianchini M, Von Euw EM, Barrio MM, Bravo AI, Furman D, et al. Human leukocyte antigen-E protein is overexpressed in primary human colorectal cancer. Int J Oncol. 2008;32(3):633–41.
Nattermann J, Nischalke HD, Hofmeister V, Kupfer B, Ahlenstiel G, Feldmann G, et al. HIV-1 infection leads to increased HLA-E expression resulting in impaired function of natural killer cells. Antivir Ther. 2005;10(1):95–107.
Kamiya T, Seow SV, Wong D, Robinson M, Campana D. Blocking expression of inhibitory receptor NKG2A overcomes tumor resistance to NK cells. J Clin Invest. 2019;129(5):2094–106.
Andre P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, et al. Anti-NKG2A mAb Is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell. 2018;175(7):1731-43 e13.
Johansson SE, Hejdeman B, Hinkula J, Johansson MH, Romagné F, Wahren B, et al. NK cell activation by KIR-binding antibody 1–7F9 and response to HIV-infected autologous cells in viremic and controller HIV-infected patients. Clin Immunol. 2010;134(2):158–68.
Dervillez X, Hüther A, Schuhmacher J, Griesinger C, Cohen JH, von Laer D, et al. Stable expression of soluble therapeutic peptides in eukaryotic cells by multimerisation: application to the HIV-1 fusion inhibitory peptide C46. ChemMedChem. 2006;1(3):330–9.
Adams P, Fievez V, Schober R, Amand M, Iserentant G, Rutsaert S, et al. CD32(+)CD4(+) memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice. iScience. 2021;24(1):101881.
Seguin-Devaux C, Plesseria JM, Verschueren C, Masquelier C, Iserentant G, Fullana M, et al. FHR4-based immunoconjugates direct complement-dependent cytotoxicity and phagocytosis towards HER2-positive cancer cells. Mol Oncol. 2019;13(12):2531–53.
Anton OM, Peterson ME, Hollander MJ, Dorward DW, Arora G, Traba J, et al. Trans-endocytosis of intact IL-15Ralpha-IL-15 complex from presenting cells into NK cells favors signaling for proliferation. Proc Natl Acad Sci U S A. 2020;117(1):522–31.
Eckelhart E, Warsch W, Zebedin E, Simma O, Stoiber D, Kolbe T, et al. A novel Ncr1-Cre mouse reveals the essential role of STAT5 for NK-cell survival and development. Blood. 2011;117(5):1565–73.
Lee WS, Richard J, Lichtfuss M, Smith AB 3rd, Park J, Courter JR, et al. Antibody-dependent cellular cytotoxicity against reactivated HIV-1-infected cells. J Virol. 2016;90(4):2021–30.
Katano I, Nishime C, Ito R, Kamisako T, Mizusawa T, Ka Y, et al. Long-term maintenance of peripheral blood derived human NK cells in a novel human IL-15- transgenic NOG mouse. Sci Rep. 2017;7(1):17230.
Prins JM, Jurriaans S, van Praag RM, Blaak H, van Rij R, Schellekens PT, et al. Immuno-activation with anti-CD3 and recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS. 1999;13(17):2405–10.
Lafeuillade A, Poggi C, Chadapaud S, Hittinger G, Chouraqui M, Pisapia M, et al. Pilot study of a combination of highly active antiretroviral therapy and cytokines to induce HIV-1 remission. J Acquir Immune Defic Syndr. 2001;26(1):44–55.
Abner E, Jordan A. HIV “shock and kill” therapy: in need of revision. Antiviral Res. 2019;166:19–34.
Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012;487(7408):482–5.
Delagrèverie HM, Delaugerre C, Lewin SR, Deeks SG, Li JZ. Ongoing clinical trials of human immunodeficiency virus latency-reversing and immunomodulatory agents. Open Forum Infect Dis. 2016;3(4):ofw189.
Kulkosky J, Culnan DM, Roman J, Dornadula G, Schnell M, Boyd MR, et al. Prostratin: activation of latent HIV-1 expression suggests a potential inductive adjuvant therapy for HAART. Blood. 2001;98(10):3006–15.
Novis CL, Archin NM, Buzon MJ, Verdin E, Round JL, Lichterfeld M, et al. Reactivation of latent HIV-1 in central memory CD4+ T cells through TLR-1/2 stimulation. Retrovirology. 2013;10:119.
Lim SY, Osuna CE, Hraber PT, Hesselgesser J, Gerold JM, Barnes TL, et al. TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy. Sci Transl Med. 2018;10(439):eaao4521.
López-Huertas MR, Jiménez-Tormo L, Madrid-Elena N, Gutiérrez C, Rodríguez-Mora S, Coiras M, et al. The CCR5-antagonist Maraviroc reverses HIV-1 latency in vitro alone or in combination with the PKC-agonist Bryostatin-1. Sci Rep. 2017;7(1):2385.
Pollard RB, Rockstroh JK, Pantaleo G, Asmuth DM, Peters B, Lazzarin A, et al. Safety and efficacy of the peptide-based therapeutic vaccine for HIV-1, Vacc-4x: a phase 2 randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2014;14(4):291–300.
Schooley RT, Spritzler J, Wang H, Lederman MM, Havlir D, Kuritzkes DR, et al. AIDS clinical trials group 5197: a placebo-controlled trial of immunization of HIV-1-infected persons with a replication-deficient adenovirus type 5 vaccine expressing the HIV-1 core protein. J Infect Dis. 2010;202(5):705–16.
García F, Climent N, Assoumou L, Gil C, González N, Alcamí J, et al. A therapeutic dendritic cell-based vaccine for HIV-1 infection. J Infect Dis. 2011;203(4):473–8.
Gay CL, DeBenedette MA, Tcherepanova IY, Gamble A, Lewis WE, Cope AB, et al. Immunogenicity of AGS-004 dendritic cell therapy in patients treated during acute HIV infection. AIDS Res Hum Retrovir. 2018;34(1):111–22.
Allard SD, De Keersmaecker B, de Goede AL, Verschuren EJ, Koetsveld J, Reedijk ML, et al. A phase I/IIa immunotherapy trial of HIV-1-infected patients with Tat, Rev and Nef expressing dendritic cells followed by treatment interruption. Clin Immunol. 2012;142(3):252–68.
Laeremans T, den Roover S, Lungu C, D’Haese S, Gruters RA, Allard SD, et al. Autologous dendritic cell vaccination against HIV-1 induces changes in natural killer cell phenotype and functionality. NPJ Vaccines. 2023;8(1):29.
Barouch DH, Whitney JB, Moldt B, Klein F, Oliveira TY, Liu J, et al. Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. Nature. 2013;503(7475):224–8.
Mendoza P, Gruell H, Nogueira L, Pai JA, Butler AL, Millard K, et al. Combination therapy with anti-HIV-1 antibodies maintains viral suppression. Nature. 2018;561(7724):479–84.
Niessl J, Baxter AE, Mendoza P, Jankovic M, Cohen YZ, Butler AL, et al. Combination anti-HIV-1 antibody therapy is associated with increased virus-specific T cell immunity. Nat Med. 2020;26(2):222–7.
Borducchi EN, Liu J, Nkolola JP, Cadena AM, Yu WH, Fischinger S, et al. Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys. Nature. 2018;563(7731):360–4.
Shi Y, Su J, Chen R, Wei W, Yuan Z, Chen X, et al. The role of innate immunity in natural elite controllers of HIV-1 infection. Front Immunol. 2022;13:780922.
Rothe A, Sasse S, Topp MS, Eichenauer DA, Hummel H, Reiners KS, et al. A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2015;125(26):4024–31.
Sarhan D, Brandt L, Felices M, Guldevall K, Lenvik T, Hinderlie P, et al. 161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS. Blood Adv. 2018;2(12):1459–69.
Huot N, Rascle P, Petitdemange C, Contreras V, Stürzel CM, Baquero E, et al. SIV-induced terminally differentiated adaptive NK cells in lymph nodes associated with enhanced MHC-E restricted activity. Nat Commun. 2021;12(1):1282.
Marçais A, Cherfils-Vicini J, Viant C, Degouve S, Viel S, Fenis A, et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol. 2014;15(8):749–57.
Naora H, Gougeon ML. Enhanced survival and potent expansion of the natural killer cell population of HIV-infected individuals by exogenous interleukin-15. Immunol Lett. 1999;68(2–3):359–67.
Parayath KE, Harrison TS, Levitz SM. Effect of interleukin (IL)-15 priming on IL-12 and interferon-gamma production by pathogen-stimulated peripheral blood mononuclear cells from human immunodeficiency virus-seropositive and -seronegative donors. J Infect Dis. 2000;181(2):733–6.
Felices M, Lenvik AJ, McElmurry R, Chu S, Hinderlie P, Bendzick L, et al. Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight. 2018. 10.1172/jci.insight.96219. DOI: 10.1172/jci.insight.96219
Hasenkamp J, Borgerding A, Wulf G, Uhrberg M, Jung W, Dingeldein S, et al. Resistance against natural killer cell cytotoxicity: analysis of mechanisms. Scand J Immunol. 2006;64(4):444–9.
Correia MP, Costa AV, Uhrberg M, Cardoso EM, Arosa FA. IL-15 induces CD8+ T cells to acquire functional NK receptors capable of modulating cytotoxicity and cytokine secretion. Immunobiology. 2011;216(5):604–12.
Ohkawa T, Seki S, Dobashi H, Koike Y, Habu Y, Ami K, et al. Systematic characterization of human CD8+ T cells with natural killer cell markers in comparison with natural killer cells and normal CD8+ T cells. Immunology. 2001;103(3):281–90.
de Araújo-Souza PS, Hanschke SC, Viola JP. Epigenetic control of interferon-gamma expression in CD8 T cells. J Immunol Res. 2015;2015:849573.
Seay K, Church C, Zheng JH, Deneroff K, Ochsenbauer C, Kappes JC, et al. In vivo activation of human NK cells by treatment with an interleukin-15 superagonist potently inhibits acute in vivo HIV-1 infection in humanized mice. J Virol. 2015;89(12):6264–74.
Veillette M, Coutu M, Richard J, Batraville LA, Dagher O, Bernard N, et al. The HIV-1 gp120 CD4-bound conformation is preferentially targeted by antibody-dependent cellular cytotoxicity-mediating antibodies in sera from HIV-1-infected individuals. J Virol. 2015;89(1):545–51.
Gooneratne SL, Richard J, Lee WS, Finzi A, Kent SJ, Parsons MS. Slaying the Trojan horse: natural killer cells exhibit robust anti-HIV-1 antibody-dependent activation and cytolysis against allogeneic T cells. J Virol. 2015;89(1):97–109.
Miller JS, Davis ZB, Helgeson E, Reilly C, Thorkelson A, Anderson J, et al. Safety and virologic impact of the IL-15 superagonist N-803 in people living with HIV: a phase 1 trial. Nat Med. 2022;28(2):392–400.
Rahman SA, Billingsley JM, Sharma AA, Styles TM, Govindaraj S, Shanmugasundaram U, et al. Lymph node CXCR5+ NK cells associate with control of chronic SHIV infection. JCI Insight. 2022. 10.1172/jci.insight.155601. DOI: 10.1172/jci.insight.155601
Sungur CM, Wang Q, Ozantürk AN, Gao H, Schmitz AJ, Cella M, et al. Human NK cells confer protection against HIV-1 infection in humanized mice. J Clin Invest. 2022. 10.1172/JCI162694. DOI: 10.1172/JCI162694
McBrien JB, Mavigner M, Franchitti L, Smith SA, White E, Tharp GK, et al. Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8(+) cells. Nature. 2020;578(7793):154–9.
McBrien JB, Wong AKH, White E, Carnathan DG, Lee JH, Safrit JT, et al. Combination of CD8beta depletion and Interleukin-15 superagonist N-803 induces virus reactivation in simian-human immunodeficiency virus-infected long-term ART-treated rhesus macaques. J Virol. 2020;94(19):10–1128.
Cartwright EK, Spicer L, Smith SA, Lee D, Fast R, Paganini S, et al. CD8(+) lymphocytes are required for maintaining viral suppression in SIV-infected macaques treated with short-term antiretroviral therapy. Immunity. 2016;45(3):656–68.
Hangasky JA, Waldmann TA, Santi DV. Interleukin 15 pharmacokinetics and consumption by a dynamic cytokine sink. Front Immunol. 2020;11:1813.
Romee R, Cooley S, Berrien-Elliott MM, Westervelt P, Verneris MR, Wagner JE, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood. 2018;131(23):2515–27.
