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There is nevertheless no cure for HIV-1 infection since HIV-1 persists in viral reservoirs of latently infected CD4<jats:sup>+<\/jats:sup> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We designed and evaluated the potency of \u201cNatural killer activating Multimeric immunotherapeutic compleXes\u201d, called as NaMiX, combining multimers of the IL-15\/IL-15R\u03b1 complex with an anti-NKG2A or an anti-KIR single-chain fragment variable (scFv) to kill HIV-1 infected CD4<jats:sup>+<\/jats:sup> T cells. The oligomerization domain of the C4 binding protein was used to associate the IL-15\/IL-15R\u03b1 complex to the scFv of each checkpoint inhibitor as well as to multimerize each entity into a heptamer (\u03b1 form) or a dimer (\u03b2 form). Each \u03b1 or \u03b2 form was compared in different in vitro models using one-way ANOVA and post-hoc Tukey\u2019s tests before evaluation in humanized NSG tg-huIL-15 mice having functional NK cells.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>All NaMiX significantly enhanced the cytolytic activity of NK and CD8<jats:sup>+<\/jats:sup> T cells against Raji tumour cells and HIV-1<jats:sup>+<\/jats:sup> ACH-2 cells by increasing degranulation, release of granzyme B, perforin and IFN-\u03b3. 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<jats:sup>+<\/jats:sup> T cells which was subsequently inhibited by cytotoxic NK cells. Importantly, anti-NKG2A NaMiX enhanced activation, cytotoxicity, IFN-\u03b3 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.\u03b1 NaMiX, as compared to control mice, as well as decreased total HIV-1 DNA in the lung.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>NK cell-mediated killing of HIV-1 infected cells by NaMiX represents a promising approach to support HIV-1 cure strategies.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12967-023-04669-4","type":"journal-article","created":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T20:01:58Z","timestamp":1699387318000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Multimeric immunotherapeutic complexes activating natural killer cells towards HIV-1 cure"],"prefix":"10.1186","volume":"21","author":[{"given":"Rafa\u00ebla","family":"Schober","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bianca","family":"Brandus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thessa","family":"Laeremans","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gilles","family":"Iserentant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camille","family":"Rolin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00e9raldine","family":"Dessilly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacques","family":"Zimmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel","family":"Moutschen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joeri L.","family":"Aerts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xavier","family":"Dervillez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0636-5222","authenticated-orcid":false,"given":"Carole","family":"Seguin-Devaux","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,11,7]]},"reference":[{"issue":"6","key":"4669_CR1","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/nm880","volume":"9","author":"JD Siliciano","year":"2003","unstructured":"Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, et al. 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