Dendritic Cell Dynamics in Peripheral and Lymphoid Tissues in SIV Infection

SIV 感染时外周组织和淋巴组织的树突状细胞动态

• 批准号: 8648972
• 负责人: Simon M Barratt-Boyes
• 金额: $ 69.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-23 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648972
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Antiviral Agents; Apoptosis; Attenuated; Blood; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; Cells; Chronic; Chronic Phase; Conflict (Psychology); Data; Dendritic Cells; Development; Disease; Disease Progression; Employee Strikes; Goals; Grant; HIV; Homing; Human; IL3RA gene; Immune; Immune response; Immune system; Individual; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; Interferons; Link; Lymphoid Tissue; Macaca; Macaca mulatta; Maintenance; Mediating; Modeling; Monkeys; Morbidity - disease rate; Mucous Membrane; Myelogenous; Natural Immunity; Outcome; Pathogenesis; Pathologic; Peripheral; Play; Public Health; Publishing; Reagent; Regulatory T-Lymphocyte; Research; Role; SIV; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; United States; Virus; Virus Diseases; Work; antiretroviral therapy; base; combat; cytokine; design; disorder control; humanized antibody; immune activation; in vivo; lymph nodes; macrophage; monocyte; mortality; nonhuman primate; novel; response; therapeutic target; virus pathogenesis

DESCRIPTION (provided by applicant): Dendritic cells (DC) and monocytes/macrophages (Mo/M¿) are innate immune cells that play a critical role in the host response to viral infection b mediating antiviral activity and inducing adaptive immune responses. However, in human immunodeficiency virus (HIV) infection of humans this relationship between DC, Mo/M¿ and virus control is not clear, as generalized immune activation that is a central feature of progression to AIDS may be driven by an overactive innate immune response to infection. Hence, a central unanswered question in HIV pathogenesis is whether the DC and Mo/M¿ response to infection is desirable or detrimental. This represents a critical impediment to progress in the field, as we do not know if therapeutic strategies should be aimed at blocking or promoting innate immunity. In this proposal we will address this central question in simian immunodeficiency virus (SIV) infection of rhesus macaques, which models HIV infection of humans. We will prospectively study the DC and Mo/M¿ response in SIVmac251-infected macaques with controlled infection vs. normal or rapid progression and compare this to macaques infected with SIVmac251 and treated with antiretroviral therapy or infected with attenuated SIVmac239¿nef. With this full spectrum of outcomes of infection we will be able to put into context the relevance of the DC and Mo/M¿ response to AIDS pathogenesis. In addition, we will use a novel humanized antibody specific for one subset of DC, the plasmacytoid DC, to deplete these cells at the time of infection or during the chronic phase. This will, for the first time, allow us to directly determine the contribution of plasmacytoid DC to virs control and chronic immune activation. These hypothesis-driven studies will further define the role of DC and Mo/M¿ in HIV infection and provide direction for development of therapeutics targeting innate immunity.

描述（由申请人提供）：树突状细胞（DC）和单核/巨噬细胞（Mo/M¿）是先天免疫细胞，在宿主对病毒感染的反应中发挥关键作用，介导抗病毒活性和诱导适应性免疫反应。然而，在人类免疫缺陷病毒（HIV）感染中，DC、Mo/M¿和病毒控制之间的关系尚不清楚，因为作为艾滋病进展的核心特征的全身免疫激活可能是由对感染的过度活跃的先天免疫反应驱动的。因此，艾滋病毒发病机制中一个悬而未决的核心问题是DC和Mo/M¿对感染的反应是可取的还是有害的。这是该领域进展的一个重大障碍，因为我们不知道治疗策略是否应该以阻断或促进先天免疫为目标。在本提案中，我们将解决猕猴猴免疫缺陷病毒（SIV）感染的核心问题，这是人类HIV感染的模型。我们将前瞻性地研究感染SIVmac251的猕猴在控制感染与正常或快速进展的情况下的DC和Mo/M反应，并将其与感染SIVmac251并接受抗逆转录病毒治疗或感染减毒SIVmac239的猕猴进行比较。有了这种全面的感染结果，我们将能够将DC和Mo/M¿应对艾滋病发病机制的相关性纳入背景。此外，我们将使用一种新的人源化抗体，专门针对DC的一个亚群，浆细胞样DC，在感染时或在慢性期消耗这些细胞。这将使我们第一次能够直接确定浆细胞样DC对病毒控制和慢性免疫激活的贡献。这些假设驱动的研究将进一步确定DC和Mo/M¿在HIV感染中的作用，并为开发针对先天免疫的治疗方法提供方向。