Granulocytic myeloid–derived suppressor cells sustain HIV reservoirs by inhibiting viral reactivation via arginase 1–mediated mechanisms
Ana Gallego-Cortés, Judith Grau-Expósito, Irene Mota-Gómez, Aleix Benitez-Martinez, Josep Castellvi, Jordi Navarro, Adrian Curran, Joaquin Burgos, Paula Suanzes, Vicenç Falcó, Meritxell Genescà, Maria J. Buzon
Ana Gallego-Cortés, Judith Grau-Expósito, Irene Mota-Gómez, Aleix Benitez-Martinez, Josep Castellvi, Jordi Navarro, Adrian Curran, Joaquin Burgos, Paula Suanzes, Vicenç Falcó, Meritxell Genescà, Maria J. Buzon
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Research Article AIDS/HIV Immunology

Granulocytic myeloid–derived suppressor cells sustain HIV reservoirs by inhibiting viral reactivation via arginase 1–mediated mechanisms

Abstract

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells with potent immunosuppressive capabilities that contribute to viral persistence in chronic infections. However, their direct effect on the latent HIV reservoir remains poorly understood. Here, we report that people with HIV (PWH) exhibit elevated levels of MDSCs with notable immunosuppressive activity. Both granulocytic (G-MDSCs) and monocytic (M-MDSCs) subsets expressing arginase 1 (ARG1) or indoleamine 2,3-dioxygenase (IDO) are increased during treated infection, with low-level viral transcription preferentially associated with the expansion of highly suppressive G-MDSCs. Functional assays revealed that G-MDSCs robustly inhibit HIV reactivation from latent reservoirs. Mechanistically, G-MDSCs mediate this inhibition through a contact-independent mechanism, primarily involving ARG1 activity. Our findings demonstrate the capacity of G-MDSCs to sustain HIV reservoirs, suggesting that targeting these cells could potentiate therapeutic strategies aimed at eliminating HIV reservoirs through viral reactivation.

Authors

Ana Gallego-Cortés, Judith Grau-Expósito, Irene Mota-Gómez, Aleix Benitez-Martinez, Josep Castellvi, Jordi Navarro, Adrian Curran, Joaquin Burgos, Paula Suanzes, Vicenç Falcó, Meritxell Genescà, Maria J. Buzon

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Figure 6

G-MDSCs decrease CD4+ T-cell activation and HIV reactivation.

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G-MDSCs decrease CD4+ T-cell activation and HIV reactivation. Ex vivo re...
Ex vivo reactivated CD4+ T cells (CD4 React) from ART PWH were cocultured overnight with G-MDSCs, after which CD4+ T cell activation and viral reactivation were measured. Graphs showing: (A and B) CD69 expression (n = 13) (A) and intracellular p24 levels (n = 8) (B) within CD4+ T cells after coculture with autologous G-MDSCs. (C) Intact HIV DNA levels in CD4+ T cells unstimulated and following reactivation in the presence or absence of autologous G-MDSCs (n = 6). (D) Impact on CD4+ T cell activation (n = 6) and p24 levels within CD4+ T cells (n = 8) when CD4+ T cells and G-MDSCs were cultured in a transwell system. (E and F) Effect of the ARG1 inhibitor nor-NOHA on CD4+ T cell activation (n = 7) (E) and intracellular p24 expression (n = 7) (F) when added to the CD4+ T cell-MDSC coculture. (G) CD69 (n = 4) and p24 expression (n = 6) in reactivated CD4+ T cells from ART PWH cultured alone or in the presence of G-MDSCs from HD individuals. In all panels, each point represents an individual donor from independent assays and lines connect paired mono- and cocultures. Circles indicate experiments in which autologous CD4+ T cells and G-MDSCs were cultured in direct contact, diamonds indicate transwell cultures, and squares represent heterologous cultures using G-MDSCs from HD individuals. All experiments were independently replicated, with each run including PBMC samples from distinct donors. Statistical comparisons were performed using 2-sided Wilcoxon tests with significance levels denoted as *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Mean values are represented in these graphs. Source data are provided as a Source Data file.