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

Abstract

Neutrophils are innate immune cells that display immunomodulatory properties by secreting cytokines and chemokines. By using a mouse model of retroviral infection, we previously uncovered the key immunomodulatory function of neutrophils in promoting protective immunity during antiviral antibody therapy which occurs in a Fc-dependent manner. Here, we investigated the immunomodulatory properties of neutrophils in the context of HIV-1 infection and therapy. We characterized the functional activation and the modulation of Fcγ receptors (FcγRs) 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 immune complexes (ICs) made with broadly neutralizing antibodies (bNAbs). Neutrophils from HD secreted cytokines/chemokines in small amount upon activation by either stimulus. Interestingly, conditioning of neutrophils from HD 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 neutrophils isolated from HD, 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.