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

• 批准号: 9058596
• 负责人: Guohua Yi
• 金额: $ 37.75万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 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/9058596
• 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; Hematopoietic; Homologous Gene; Human; ITIM; Immune; Immune System Diseases; Individual; Inflammation; Intervention; Length; Literature; Lymphocyte; Mediating; Methods; Modeling; Mucous Membrane; Mus; Pathogenesis; Pathogenicity; Peptides; Plasma; Play; Process; RNA Interference; Reporting; Risk; Role; Sepsis; Serum; Signal Transduction; Small Interfering RNA; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Tyrosine; Up-Regulation; Viral Load result; Viremia; Virus Replication; antiretroviral therapy; apoptosis in lymphocytes; base; cytokine; disorder risk; human subject; humanized mouse; immune activation; in vivo; macrophage; member; monocyte; mortality; mouse model; new therapeutic target; novel; overexpression; pre-clinical; public health relevance; rabies virus glycoprotein G; receptor

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（应用程序提供）：摘要：即使在抗逆转录病毒疗法中也可以持续存在的慢性免疫激活是HIV感染中疾病进展的有力预测指标。了解慢性免疫学激活的机制可能有助于确定HIV感染中治疗干预措施的新靶标。来自文献的大量证据表明，HIV疾病直接或间接地激活单核细胞/巨噬细胞，以秘密促炎性细胞因子在这种致病性免疫激活中起主要作用。众所周知，来自HIV感染个体的单核细胞是赞助的秘密细胞因子，尽管涉及的分子的机制尚不清楚。 PD-1H是B7/CD28共刺激和共抑制受体家族的新成员，到目前为止，在人类中尚未表征。迄今为止的数据表明，该分子可能来自与所有其他B7家族成员不同的前体。尽管在B7/CD28家族中，PD-1H的全长序列与负调控分子PD-1具有最高的相似性，与PD-1不同，PD-1H的细胞质结构域不含基于免疫感受器的抑制性抑制性基序（ITIM）或ImmunoreCeptor the Impoctopptor腐败（ITS-ITS-INS-BAINS-ITYES-TUROSECERINE TYEROSINE SELLIF（ITSM）。我们的初步数据表明，PD-1H在单核细胞上表达较高的造血细胞上广泛表达。人类单核细胞中PD-1H的过度表达足以诱导多种细胞因子的赞助。此外，来自HIV感染个体的单核细胞过表达PD-1H，与单核细胞中的细胞因子基因表达相关，而T细胞上的免疫激活标记不与病毒载量相关。基于这些数据，我们假设PD-1H充当单核细胞激活分子，在HIV发病机理中起主要作用。在此提案中，我们将使用来自HIV疾病阶段的PBMC和人源化的BLT模型来评估ART如何影响这一过程，这些PBMC概括了HIV发病机理的关键特征，包括免疫激活。我们的具体目的是：1）使用已定义的HIV感染个体的群体来表征与免疫激活，血浆促炎细胞因子水平，CD4 T细胞定义和血浆病毒血症相关的PD-1H的进化。 2）表征人性化BLT小鼠在病毒载荷，CD4 T细胞计数和由单核细胞相关的生物标志物/细胞因子和T细胞上激活标记定义的HIV感染过程中不同时间点的PD-1H表达。我们还将测试ART后的PD-1H表达如何变化，与其他参数有关，以及3）测试人源性小鼠中的沉默PD-1H或相关分子是否会逆转免疫激活或影响或没有ART的HIV感染的其他参数。