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

基本信息

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
项目类别：
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

项目摘要

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）和单核细胞/巨噬细胞（Mo/MK）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，介导抗病毒活性并诱导适应性免疫反应。在人类免疫缺陷病毒 (HIV) 感染中，DC、Mo/M 之间的关系病毒控制尚不清楚，因为全身免疫激活是艾滋病进展的一个核心特征，可能是由对感染的过度活跃的先天免疫反应驱动的。因此，HIV 发病机制中一个未解答的核心问题是 DC 和 Mo/M 是否存在。对感染的反应是理想的还是不健康的，这是该领域进展的一个关键障碍，因为我们不知道治疗策略是否应该旨在阻止或促进先天免疫。在本提案中，我们将解决猿猴免疫缺陷病毒的这一核心问题。 (SIV) 恒河猴感染，模拟人类 HIV 感染我们将前瞻性地研究 DC 和 Mo/M¿感染受控感染的 SIVmac251 猕猴与正常或快速进展的反应，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。有了这些完整的感染结果，我们将能够将 DC 和 Mo/M 的相关性纳入背景。此外，我们将使用一种针对 DC 子集（浆细胞样 DC）的新型人源化抗体，在感染时或慢性期消除这些细胞。我们可以直接确定浆细胞样 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 的作用。并为针对先天免疫的治疗方法的开发提供方向。