Neutrophil-mediated immune suppression as a mechanism of HIV-1 pathogenesis.

描述（由申请人提供）：在自然史和抗逆转录病毒治疗中，慢性免疫激活和T细胞功能能力的丧失是HIV-1感染的关键标志。HIV-1与宿主免疫系统之间相互作用的许多方面尚不清楚。精确描述这些机制对于我们理解HIV-1发病机制和设计新疗法至关重要。来自hiv -1感染个体的CD4+和CD8+ T细胞表现出对抗原刺激的反应性降低、产生细胞因子的能力下降和程序性死亡-1 （PD-1）分子表面水平升高。PD-1与其配体PD-L1的结合导致T细胞无能表型的诱导。微生物易位、免疫激活和T细胞功能丧失之间关系的确切机制尚不完全清楚。在这里，我们提出中性粒细胞亚群，可能被细菌易位的产物激活，代表了HIV-1感染中一个主要的免疫抑制群体，对T细胞具有有效的抑制活性。我们发现hiv -1感染个体的外周血中性粒细胞表达PD- L1水平升高，并抑制抗原特异性和非特异性T细胞反应。pbmc中中性粒细胞的消耗导致抗原特异性T细胞增殖和细胞因子产生的显著增加。中性粒细胞抑制T细胞功能的机制尚不清楚；然而，初步数据表明，它是介导的

DESCRIPTION (provided by applicant): 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.