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

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.