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。

基本信息

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
项目类别：
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

项目摘要

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 细胞功能丧失是自然史和抗逆转录病毒治疗下 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。准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。 HIV-1 感染者的 CD4+ 和 CD8+ T 细胞对抗原刺激的反应性降低，产生细胞因子的能力降低，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 的结合会导致 T 细胞产生无能表型。微生物易位、免疫激活和 T 细胞功能丧失之间关系的精确机制尚不完全清楚。在这里，我们提出，中性粒细胞亚群可能由细菌易位产物激活，代表 HIV-1 感染中的主要免疫抑制群体，对 T 细胞发挥有效的抑制活性。我们发现，HIV-1 感染者的外周血中性粒细胞表达升高水平的 PD-L1，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 细胞的增殖和细胞因子产生显着增加。中性粒细胞抑制T细胞功能的机制尚不清楚；但初步数据显示，这是经过调解的 PD-L1 和活性氧 (ROS) 的产生。我们提出了一种新的、尚未被认识的 HIV-1 感染者免疫抑制机制。重要的是，我们的数据表明抑制性中性粒细胞是由微生物易位和/或病毒颗粒的产物诱导的。因此，我们假设中性粒细胞介导的 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。为了进一步表征这一新途径在 HIV-1 发病机制中的作用，我们建议定义中性粒细胞介导的免疫抑制机制以及 HIV-1 感染者中中性粒细胞激活和诱导抑制表型的机制。本研究中测试的新型免疫抑制模型可能会显着改变我们对 HIV-1 发病机制的理解，并导致针对 HIV-1 感染者免疫功能丧失的新型疗法的设计。