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HIV-Induced Immune Activation in Humanized MIce

HIV 诱导的人源化小鼠免疫激活

基本信息

批准号：
8662200
负责人：
MANJUNATH NARASIMHA SWAMY
金额：
$ 22.65万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
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：
2013-05-16 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8662200
关键词：
Arginine Bacterial Translocation Binding Blood Circulation CD4 Positive T Lymphocytes Cholinergic Receptors Chronic Cytokine Activation Dendritic Cells Dengue Virus Disease Disease Progression HIV HIV Infections HMGB1 gene Human IL8 gene Immune Immune System Diseases Immune response Individual Infection Inflammation Mediators Inflammatory Interleukin-1 Interleukin-6 Intestines Ligands Lymphocyte Mediating Mucous Membrane Mus Nucleic Acids Peptides Phenotype Reporting Risk Role Sepsis Serum Small Interfering RNA T-Lymphocyte TNF gene Testing Toll-like receptors Viral Viral Load result Viral Proteins Viremia apoptosis in lymphocytes base cell type cytokine immune activation in vivo macrophage microbial monocyte mortality mouse model public health relevance rabies virus glycoprotein G receptor for advanced glycation endproducts targeted delivery toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): Persistent immune activation is a strong predictor of disease progression in HIV infection and is characterized by activation of all immune cell types, increased levels of proinflammatory cytokines and activation-induced lymphocyte apoptosis. Translocation of microbial toll-like receptor (TLR) ligands from the gut to the systemic circulatio has been recognized in recent years to be a major factor in inducing immune activation. The resulting increase in inflammatory cytokines may be the fundamental cause for immune activation and determinant of disease progression. The cytokine storm, immune activation and lymphocyte apoptosis attended with microbial products in systemic circulation seen in HIV infection also characterizes natural and experimental sepsis. HMGB1 secreted from macrophages and dendritic cells acts as a master regulator of cytokine storm in sepsis. We have recently shown that silencing HMGB1 in human macrophages and dendritic cells in vivo in humanized BLT mice by targeted delivery of siRNA (via a peptide called RVG-9R) dramatically suppressed the sepsis-induced cytokine storm and mortality. Although serum level of HMGB1 as well as downstream cytokines are also elevated in HIV infected individuals, their role in chronic immune activation is not clear. In this proposal, we will test the role of HMGB1 and downstream cytokines, their relation to microbial products and the effect of suppressing these inflammatory mediators on immune activation and disease progression in vivo using the humanized mouse model for HIV infection. In Aim 1, we will characterize the full spectrum of immune activation in HIV infected humanized mice without or with ART. In the second aim we will test if silencing HMGB1 or downstream cytokines by targeted delivery of siRNA to macrophages and dendritic cells can reduce immune activation and disease progression in infected mice.

描述（由申请方提供）：持续性免疫激活是HIV感染中疾病进展的有力预测因子，其特征为所有免疫细胞类型的激活、促炎细胞因子水平升高和激活诱导的淋巴细胞凋亡。近年来，微生物Toll样受体（TLR）配体从肠道向体循环的转运被认为是诱导免疫激活的主要因素。由此导致的炎性细胞因子的增加可能是免疫激活的根本原因和疾病进展的决定因素。在HIV感染中观察到的细胞因子风暴、免疫激活和淋巴细胞凋亡伴随着体循环中的微生物产物也是自然和实验性脓毒症的特征。由巨噬细胞和树突状细胞分泌的HMGB 1作为脓毒症中细胞因子风暴的主要调节剂。我们最近已经表明，通过靶向递送siRNA（通过称为RVG-9 R的肽）在人源化BLT小鼠体内的人巨噬细胞和树突状细胞中沉默HMGB 1显著抑制了脓毒症诱导的细胞因子风暴和死亡率。虽然HMGB 1和下游细胞因子的血清水平也在HIV感染者中升高，但它们在慢性免疫激活中的作用尚不清楚。在这个提议中，我们将测试HMGB 1和下游细胞因子的作用，它们与微生物产物的关系，以及使用HIV感染的人源化小鼠模型在体内抑制这些炎症介质对免疫激活和疾病进展的影响。在第一个目标中，我们将描述HIV感染的人源化小鼠中免疫激活的全谱，而不使用或使用ART。在第二个目标中，我们将测试通过靶向递送siRNA至巨噬细胞和树突状细胞来沉默HMGB 1或下游细胞因子是否可以减少感染小鼠中的免疫激活和疾病进展。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Characterization of programmed death-1 homologue-1 (PD-1H) expression and function in normal and HIV infected individuals.

DOI：
10.1371/journal.pone.0109103
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Bharaj P;Chahar HS;Alozie OK;Rodarte L;Bansal A;Goepfert PA;Dwivedi A;Manjunath N;Shankar P
通讯作者：
Shankar P

Targeting DNA vaccines to myeloid cells using a small peptide.