Abstract
The discovery of broadly neutralizing antibodies against HIV-1 (bNAbs) has positioned passive immunotherapy as a potential curative approach. Beyond their virus-neutralizing capabilities, bNAbs enhance both humoral and cellular immune responses, a phenomenon known as the vaccinal effect. However, the mechanisms underlying this effect remain unclear. In a mouse model of retroviral infection, we demonstrated that the induction of vaccinal effects by monoclonal antibodies relies on the formation of immune complexes (ICs) and their interaction with Fcγ receptors (FcγRs) on various immune cells (1). Among these cells, neutrophils play a crucial role in enhancing the antiviral response by activating and recruiting other immune cells through cytokine and chemokine secretion. Previously, we identified the key immunomodulatory role of mouse neutrophils in promoting protective immunity during antiviral antibody therapy, which occurs in an Fc-dependent manner (2). In this study, we investigated the immunomodulatory properties of human neutrophils in the context of HIV-1 infection and therapy. In particular, we characterized the functional activation and the modulation of Fcγ receptor (FcγR) expression on neutrophils isolated from healthy donors (HD) or people living with HIV-1 (PLWH) upon stimulation with virions, free or in the form of ICs made with bNAbs. HD’s neutrophils secreted cytokines/chemokines in small amount upon activation by either stimulus. Interestingly, conditioning of HD’s neutrophils with pro-inflammatory cytokines enhanced their cytokine/chemokine production upon activation by HIV-1 and ICs, highlighting that the inflammatory environment is key for neutrophils to show a functional response to these stimuli. Noteworthy, under inflammatory conditions, IC-activated neutrophils showed higher secretion of CXCL1 and CCL4 than HIV-1-stimulated neutrophils. Importantly, neutrophils from PLWH on antiretroviral treatment (ART) maintained their cytokine/chemokine secretion abilities when stimulated by TLR agonists, TNFα or HIV-1/ICs. However, they displayed different phenotypic features as compared with HD’s neutrophils, notably higher expression of FcγRs. Our study provides new insights into the immunomodulatory properties of neutrophils during HIV-1 infection and therapy. This might contribute to the improvement of antiviral antibody therapies through the use of therapeutic approaches exploiting the immunomodulatory properties of these cells.