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

中性粒细胞介导的免疫抑制是 HIV-1 发病机制的一个机制。

• 批准号: 8651885
• 负责人: Zdenek Hel
• 金额: $ 18.38万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8651885
• 关键词: Activities of Daily Living; Antigens; Bacterial Translocation; Binding; Blood; Blood Circulation; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Count; Cell physiology; Cessation of life; Chronic; Clinical; Data; Dependency; Disseminated Malignant Neoplasm; Dose; Exhibits; HIV; HIV-1; Human Volunteers; ITGAM gene; Immune; Immune system; Immunosuppression; In Vitro; Individual; Infection; Injection of therapeutic agent; Integrins; Interferons; Ligands; Macrophage-1 Antigen; Mediating; Modeling; Natural History; Neutrophil Activation; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Population; Process; Production; Property; Reactive Oxygen Species; Reporting; Role; Stimulus; Surface; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Viral; Viral Load result; Virion; Whole Blood; antiretroviral therapy; arginase; base; cytokine; density; design; exhaustion; immune activation; immune function; in vivo; microbial; neutrophil; novel; particle; peripheral blood; programs; public health relevance; volunteer

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.

描述（由申请人提供）：慢性免疫激活和T细胞功能丧失是HIV-1感染的关键特征，无论是在自然史中还是在抗逆转录病毒治疗中。HIV-1和宿主免疫系统之间相互作用的许多方面都知之甚少。这些机制的精确描述对于我们理解HIV-1发病机制和设计新的治疗方法至关重要。来自HIV-1感染个体的CD 4+和CD 8 + 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降低和程序性死亡-1（PD-1）分子的表面水平升高。PD-1与其配体PD-L1的结合导致T细胞中无反应性表型的诱导。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未完全了解。在这里，我们提出中性粒细胞亚群可能被细菌移位产物激活，代表了HIV-1感染中主要的免疫抑制群体，对T细胞发挥着强有力的抑制活性。我们发现，HIV-1感染者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。从PBMC中消耗嗜中性粒细胞导致抗原特异性T细胞的增殖和细胞因子产生显著增加。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。 PD-L1和活性氧（ROS）的产生。我们提出了一种新的，尚未认识到的免疫抑制机制，在HIV-1感染者。重要的是，我们的数据表明，抑制性中性粒细胞诱导的微生物易位和/或病毒颗粒的产品。因此，我们假设嗜中性粒细胞介导的T细胞功能抑制 代表HIV-1感染中免疫抑制的主要机制，而不是免疫失调的继发效应。为了进一步描述这种新途径在HIV-1发病机制中的作用，我们建议定义嗜中性粒细胞介导的免疫抑制机制和中性粒细胞活化机制，以及HIV-1感染者抑制表型的诱导机制。本研究中测试的免疫抑制新模型可能会显著改变我们对HIV-1发病机制的理解，并导致设计针对HIV-1感染者免疫功能丧失的新疗法。