Enhanced Fc Receptor expression and distinct immunomodulatory properties of neutrophils during HIV-1 infection and therapy

Neutrophils are innate immune cells with key immunomodulatory functions. In a murine retroviral model, we previously showed their essential role in promoting protective immunity during antiviral antibody therapy via Fc–Fcγ receptor (FcγR) interactions. Here, we investigated the immunomodulatory properties of neutrophils in the context of HIV-1 infection and therapy through a comprehensive analysis of their functional activation and the regulation of FcγR expression. Neutrophils from healthy donors (HD) and people living with HIV-1 (PLWH) were stimulated with TLR ligands, free HIV-1, immune complexes (ICs) formed with broadly neutralizing antibodies (bNAbs), or pro-inflammatory cytokines (TNFα, IFNγ). In response, they secreted various cytokines and chemokines that can recruit and activate immune cells in a stimulus-dependent manner. Compared to TLR agonist and cytokine activation, HD neutrophils showed limited cytokine production in response to free HIV-1 or ICs alone as well as a minimal FcγR modulation. However, PLWH neutrophils showed heightened responsiveness to microbial stimuli linked to HIV-1 pathogenesis, secreting higher levels of IFNγ, CXCL1, CCL2, CCL3, and CCL4. They also expressed higher levels of two activating FcγRs (FcγRI and FcγRIIIb), as well as CD11b, CD63, CXCR4, and PD-L1, indicating an altered activation state. These findings highlight the influence of the inflammatory milieu on neutrophil function and FcγR regulation in HIV-1 infection and mAb-based therapies.