Role of p38 MAPK activation in AIDS pathogenesis

p38 MAPK 激活在 AIDS 发病机制中的作用

基本信息

批准号：
8731523
负责人：
ANNA ALDOVINI
金额：
$ 88.2万
依托单位：
BOSTON CHILDREN'S HOSPITAL
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：
2014-03-01 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8731523
关键词：
Acquired Immunodeficiency Syndrome Adverse effects Affect Animals Antibodies Antigen-Presenting Cells Biological Preservation Brain CCR5 gene CD4 Positive T Lymphocytes CD8B1 gene Cause of Death Cell Lineage Cells Cercocebus atys Cercopithecus pygerythrus Clinical Trials Confocal Microscopy Data Dendritic Cells Disease Disease Progression Evaluation Flow Cytometry Gene Activation Gene Expression Gene Expression Profiling Gene Targeting Genes Goals HIV HIV Infections HIV-1 Human Image Analysis Immune response Immunohistochemistry In Vitro Individual Infection Inflammation Inflammatory Integrase Interferons Interruption Intervention Intestines Investigation Kinetics Light Link MAP Kinase Gene MAPK14 gene Macaca Maintenance Maps Measures Mediating Methods Mitogen-Activated Protein Kinase Inhibitor Molecular Profiling Mononuclear Mucous Membrane Pathogenesis Pathology Pathway interactions Peptide Hydrolases Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Plasma Play Population Primates Production Proteins Regimen Reporting Resistance Role SIV Safety Sampling Serum Markers Signal Pathway Sorting - Cell Movement Staining method Stains Superantigens Surface Surrogate Markers T-Cell Activation T-Lymphocyte Testing Tissues Viral Viral Antigens Viral Load result Viremia Virus Virus Diseases Work antiretroviral therapy brain tissue chemokine cytokine human disease immune activation in vivo inhibitor/antagonist interest lymph nodes macrophage memory CD4 T lymphocyte monocyte nervous system disorder nonhuman primate public health relevance rectal research study transcription factor treatment effect

项目摘要

DESCRIPTION (provided by applicant): Differences in immune activation have been identified as the single most significant difference between AIDS- susceptible and resistant species. Immune activation can be induced by a variety of mechanisms, including stimulation of immune responses by viral antigens, production of a superantigen, and/or production of activating cytokines and chemokines. It is quite likely that more than one mechanism is occurring simultaneously during HIV infection. We have shown that HIV and SIV infections modulates primate APC and T-cell gene expression and that at least a subset of the IFN-stimulated genes (ISG), reprogrammed in infected human and RM iDC, are not affected by SIV infection in APC of AIDS resistant species. We postulated that induction and maintenance of immune activation could depend on the induction by HIV or SIV of cell pathways leading to the production of immunoactivating cytokines and chemokines and have shown that this is the case in vitro. p38 MAPK, which has been reported to be activated in HIV and SIV infection, is key in the pathway of induction of ISG and is associated in vivo with the some of the pathology produced by HIV and SIV infection in AIDS susceptible primates. As inhibitors of p38 MAPK are available and currently tested in human trials for other diseases, we intend to evaluate the effects of treating SIV-infected macaques with a p38 inhibitor that has been shown to reduce immune activation in trials for different human diseases in conjunction with ART. Our goals are: 1 to evaluate in vivo the impact that PH-797804 alone or added to ART has on immune activation in SIV- infected RM. As primary end points we will evaluate expression of surface and intracellular molecules linked to immune activation and gene expression profiles in RM PBMC, lymph node and rectal mononuclear cell (MNC) subpopulations, and plasma levels of inflammatory cytokines and chemokines; 2. to evaluate the effects that treatments have on viral loads, viral reservoirs, and preservation of central memory CD4+ T cells as secondary end points; 3. to evaluate the treatment impact on protein levels of selected IGS and on immune activation markers in lymph node, intestinal tissue and brain sections.

描述（由申请人提供）：免疫激活的差异已被确定为艾滋病易感性和抗性物种之间最显着的差异。免疫激活可以通过多种机制诱导，包括通过病毒抗原刺激免疫应答、产生超抗原、和/或产生活化细胞因子和趋化因子。在艾滋病毒感染过程中很可能有不止一种机制同时发生。我们已经证明，HIV 和 SIV 感染调节灵长类 APC 和 T 细胞基因表达，并且在受感染的人和 RM iDC 中重新编程的至少一部分 IFN 刺激基因 (ISG) 不受 APC 中 SIV 感染的影响。艾滋病抗性物种。我们假设免疫激活的诱导和维持可能取决于 HIV 或 SIV 细胞途径的诱导，从而导致免疫激活细胞因子和趋化因子的产生，并且已经证明体外情况就是如此。据报道，p38 MAPK 在 HIV 和 SIV 感染中被激活，是 ISG 诱导途径的关键，并且在体内与 AIDS 易感灵长类动物中 HIV 和 SIV 感染产生的一些病理学相关。由于 p38 MAPK 抑制剂已经可用，并且目前正在针对其他疾病的人体试验中进行测试，因此我们打算评估使用 p38 抑制剂治疗 SIV 感染的猕猴的效果，该抑制剂已在针对不同人类疾病的试验中被证明可以减少免疫激活，并与艺术。我们的目标是： 1 体内评估单独使用 PH-797804 或添加到 ART 中对 SIV 感染 RM 免疫激活的影响。作为主要终点，我们将评估 RM PBMC、淋巴结和直肠单核细胞 (MNC) 亚群中与免疫激活相关的表面和细胞内分子的表达和基因表达谱，以及炎症细胞因子和趋化因子的血浆水平； 2. 以评估治疗对病毒载量、病毒库和中央记忆 CD4+ T 细胞保存的影响作为次要终点； 3.评估治疗对选定IGS的蛋白质水平以及对淋巴结、肠组织和脑切片中的免疫激活标志物的影响。