Role of PD-1H mediated monocyte activation in HIV pathogenesis

PD-1H 介导的单核细胞激活在 HIV 发病机制中的作用

基本信息

批准号：
8906933
负责人：
Premlata Shankar
金额：
$ 37.18万
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：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8906933
关键词：
Affect Arginine Binding Biological Markers CD28 gene CD4 Positive T Lymphocytes Cardiovascular Diseases Cell Count Cells Charge Cholinergic Receptors Chronic Cytokine Activation Cytokine Gene Cytoplasmic Tail Data Disease Disease Progression Evolution Family Family member Gene Expression HIV HIV Infections HLA-DR Antigens HMGB1 gene Health Hematopoietic Homologous Gene Human ITIM Immune Immune System Diseases Individual Inflammation Intervention Length Literature Lymphocyte Mediating Methods Modeling Mucous Membrane Mus Pathogenesis Peptides Plasma Play Process RNA Interference Reporting Risk Role Sepsis Serum Signal Transduction Small Interfering RNA Staging System T-Cell Activation T-Cell Depletion T-Lymphocyte Testing Therapeutic Intervention Time Tyrosine Up-Regulation Viral Viral Load result Viremia abstracting antiretroviral therapy apoptosis in lymphocytes base cytokine human subject immune activation in vivo macrophage member monocyte mortality mouse model novel overexpression pre-clinical rabies virus glycoprotein G receptor

项目摘要

DESCRIPTION (provided by applicant): Abstract: Chronic immune activation, which can persist even with antiretroviral therapy, is the strongest predictor of disease progression in HIV infection. Understanding the mechanism of chronic immune activation may help identify novel targets for therapeutic interventions in HIV-infection. Extensive evidence from literature suggests that HIV disease directly or indirectly activates monocyte/macrophages to secrete proinflammatory cytokines which play a major role in this pathogenic immune activation. Monocytes from HIV infected individuals are known to secrete cytokines spontaneously, although the mechanism for this or the molecules involved are not known. PD-1H is a newly discovered member of the B7/CD28 family of costimulatory and coinhibitory receptors, which has not been characterized in humans so far. Data to date suggest that the molecule may be derived from a different precursor than all other B7 family members. Although, amongst the B7/CD28 family, the full length sequence of PD-1H has the highest similarity to the negative regulatory molecule PD-1, unlike PD-1, the cytoplasmic domain of PD-1H does not contain the immunoreceptor tyrosine-based inhibitory motif (ITIM) or the immunoreceptor tyrosine-based switch motif (ITSM). Our preliminary data shows that PD- 1H is broadly expressed on hematopoietic cells with higher levels of expression on monocytes. Enforced overexpression of PD-1H in human monocytes is sufficient to induce spontaneous secretion of multiple cytokines. Further, monocytes from HIV-infected individuals overexpress PD-1H which correlates with cytokine gene expression in monocytes and immune activation markers on T cells but not with viral load. Based on these data, we hypothesize that PD-1H acts as a monocyte activation molecule that plays a major role in HIV pathogenesis. In this proposal we will test this hypothesis and evaluate how ART influences this process using PBMCs from defined stages of HIV disease and humanized BLT model which recapitulates key features of HIV pathogenesis, including immune activation. Our specific aims are to: 1) To characterize the evolution of PD-1h over expression in relation to immune activation, plasma proinflammatory cytokine levels, CD4 T cell depletion and plasma viremia using defined groups of HIV infected individuals. 2) Characterize PD-1H expression at different time points during the course of HIV infection in humanized BLT mice vis-�-vis viral load, CD4 T cell counts and immune activation defined by monocyte associated biomarkers/cytokines and activation markers on T cells. We will also test how PD-1H expression changes after ART, in relation to other parameters and 3) Test if silencing PD-1H or related molecules in humanized mice reverses immune activation or affects other parameters of HIV infection with or without ART.

描述（由申请人提供）：摘要：慢性免疫激活即使在抗逆转录病毒治疗下也能持续存在，是 HIV 感染疾病进展的最强预测因素，了解慢性免疫激活的机制可能有助于确定 HIV 治疗干预的新靶点。文献中的大量证据表明，HIV 疾病直接或间接激活单核细胞/巨噬细胞分泌促炎细胞因子，已知这些细胞因子在这种致病性免疫激活中发挥着重要作用。 PD-1H 是 B7/CD28 共刺激和共抑制受体家族中新发现的成员，但迄今为止尚未在人类中得到表征。表明该分子可能源自与所有其他 B7 家族成员不同的前体，尽管在 B7/CD28 家族中，PD-1H 的全长序列与负调节分子 PD-1 具有最高的相似性。 PD-1（PD-1H 的胞质结构域）不包含基于免疫受体酪氨酸的抑制基序（ITIM）或基于免疫受体酪氨酸的开关基序（ITSM）。我们的初步数据表明，PD-1H 在造血细胞上广泛表达。在单核细胞中强制过度表达 PD-1H 足以诱导多种细胞因子的自发分泌。 HIV 感染者过度表达 PD-1H，其与单核细胞中的细胞因子基因表达和 T 细胞上的免疫激活标记物相关，但与病毒载量无关。根据这些数据，我们发现 PD-1H 作为单核细胞激活分子发挥着重要作用。在本提案中，我们将测试这一假设，并使用来自 HIV 疾病特定阶段的 PBMC 和人源化 BLT 模型来评估 ART 如何影响这一过程，该模型概括了 HIV 发病机制的关键特征，包括我们的特定免疫激活。目的是： 1) 使用特定的 HIV 感染个体组来表征 PD-1h 过度表达与免疫激活、血浆促炎细胞因子水平、CD4 T 细胞耗竭和血浆病毒血症之间的关系。 2) 表征 PD-1H 的表达。我们还将测试人源化 BLT 小鼠 HIV 感染过程中的不同时间点的病毒载量、CD4 T 细胞计数和由单核细胞相关生物标志物/细胞因子和 T 细胞激活标志物定义的免疫激活。 ART 后 PD-1H 表达发生变化，与其他参数相关；3) 测试在人源化小鼠中沉默 PD-1H 或相关分子是否会逆转免疫激活或影响 HIV 感染的其他参数（无论有或没有 ART）。