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：
8811918
负责人：
ANNA ALDOVINI
金额：
$ 86.48万
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/8811918
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 Health 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 quantitative imaging 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AIDS易感和抗性物种之间最重要的差异。免疫激活可以通过多种机制诱导，包括病毒抗原对免疫反应的刺激，超抗原的产生和/或产生激活的细胞因子和趋化因子。在艾滋病毒感染期间，很可能会同时发生一种机制。我们已经表明，HIV和SIV感染调节了灵长类动物APC和T细胞基因表达，并且至少在受感染的人和RM IDC中重编程的IFN刺激基因（ISG）的至少子集不受抗AIDS抗性物种APC的SIV感染的影响。我们假设，免疫激活的诱导和维持可能取决于艾滋病毒或SIV的诱导，导致细胞因子和趋化因子的产生产生，并表明体外情况就是这种情况。据报道，p38 MAPK在HIV和SIV感染中被激活，是ISG诱导途径的关键，在体内与HIV和SIV感染在AIDS易感灵长类动物中产生的一些病理相关。由于可以使用p38 MAPK的抑制剂并目前在其他疾病的试验中进行了测试，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，p38抑制剂已被证明可以减少与ART结合不同人类疾病的试验中的免疫激活。我们的目标是：1在体内评估仅PH-797804或对ART添加的影响对SIV感染RM中的免疫激活的影响。作为主要终点，我们将评估与RM PBMC，淋巴结和直肠单核细胞（MNC）亚群以及炎性细胞因子和趋化因子和趋化因子和趋化因子和趋化因子和炎症的血浆水平相关的与免疫激活和基因表达谱相关的表面和细胞内分子的表达； 2。评估治疗对病毒载荷，病毒储层和中央记忆CD4+ T细胞保存的影响； 3。评估治疗对选定Ig的蛋白质水平以及淋巴结，肠组织和脑切片中免疫激活标记的影响。