| First Author | Schober R | Year | 2023 |
| Journal | J Transl Med | Volume | 21 |
| Issue | 1 | Pages | 791 |
| PubMed ID | 37936122 | Mgi Jnum | J:353767 |
| Mgi Id | MGI:7640315 | Doi | 10.1186/s12967-023-04669-4 |
| Citation | Schober R, et al. (2023) Multimeric immunotherapeutic complexes activating natural killer cells towards HIV-1 cure. J Transl Med 21(1):791 |
| abstractText | 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-15Ralpha 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-15Ralpha complex to the scFv of each checkpoint inhibitor as well as to multimerize each entity into a heptamer (alpha form) or a dimer (beta form). Each alpha or beta 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-gamma. 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-gamma 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.alpha 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. |
