Chronic immune activation and loss of T cell functional capacity are critical hallmarks of HIV-1 infection both in natural history and under antiretroviral therapy. Many aspects of the interaction between HIV-1 and the host immune system are poorly understood. Precise delineation of these mechanisms is critical for our understanding of HIV-1 pathogenesis and design of novel therapies. CD4+ and CD8+ T cells from HIV-1-infected individuals exhibit decreased responsiveness to antigenic stimuli, decreased capacity to produce cytokines and elevated surface levels of programmed death-1 (PD-1) molecule. The binding of PD-1 to its ligand PD-L1 results in an induction of anergic phenotype in T cells. Precise mechanisms underlying the relationship between microbial translocation, immune activation and loss of T cell function are not fully understood. In here we propose that a subpopulation of neutrophils, likely activated by the products of bacterial translocation, represents a major immune suppressive population in HIV-1 infection exerting a potent inhibitory activity on T cells. We show that peripheral blood neutrophils from HIV-1-infected individuals express elevated levels of PD- L1 and suppress antigen-specific and non-specific T cell responses. Depletion of neutrophils from PBMCs results in a marked increase in the proliferation and cytokine production by antigen-specific T cells. The mechanism of inhibition of T cell function by neutrophils is unclear;however preliminary data indicate that it is mediated by PD-L1 and production of reactive oxygen species (ROS). We present a novel, as yet unrecognized mechanism of immune suppression in HIV-1-infected individuals. Importantly, our data suggest that suppressive neutrophils are induced by the products of microbial translocation and/or viral particles. Thus, we hypothesize that neutrophil-mediated inhibition of T cell function represents a primary mechanism of immune suppression in HIV-1 infection and not a secondary effect of immune dysregulation. To further characterize the role of this novel pathway in HIV-1 pathogenesis, we propose to define the mechanisms of neutrophil-mediated immune suppression and the mechanisms of neutrophil activation and induction of suppressor phenotype in HIV-1-infected individuals. The novel model of immune suppression tested in this study may significantly alter our understanding of HIV-1 pathogenesis and result in a design of novel therapies targeting the loss of immune function in HIV-1-infected individuals.
We propose that chronic immune activation and microbial translocation in HIV-1 infection result in an induction of a neutrophil population with potent abilty to suppress T cell function. The novel model of immune suppression mediated by neutrophils tested in this study may significantly alter our understanding of HIV-1pathogenesis and result in a design of novel therapies targeting loss of immune function in HIV-1- infected individuals.
|Bowers, Nathan L; Helton, E Scott; Huijbregts, Richard P H et al. (2014) Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway. PLoS Pathog 10:e1003993|