Role of p38 MAPK activation in AIDS pathogenesis

p38 MAPK 激活在 AIDS 发病机制中的作用

• 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
• 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

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和耐药物种之间最显著的差异。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反应，产生超抗原，和/或产生活化细胞因子和趋化因子。在艾滋病毒感染期间，很可能同时发生不止一种机制。我们已经证明，HIV和SIV感染可以调节灵长类动物APC和t细胞基因的表达，并且至少有一部分ifn刺激基因（ISG）在受感染的人类和RM iDC中重新编程，不受艾滋病抗性物种APC中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HIV或SIV诱导的细胞通路，导致免疫激活细胞因子和趋化因子的产生，并且已经在体外证明了这种情况。p38 MAPK已被报道在HIV和SIV感染中被激活，是诱导ISG通路的关键，并且在体内与艾滋病易感灵长类中HIV和SIV感染产生的一些病理相关。由于p38 MAPK抑制剂是可用的，并且目前在其他疾病的人体试验中进行了测试，我们打算评估用p38抑制剂治疗siv感染的猕猴的效果，p38抑制剂在与ART联合治疗不同人类疾病的试验中已被证明可以降低免疫激活。我们的目标是：1 .在体内评估PH-797804单独使用或与ART联合使用对SIV感染RM的免疫激活的影响。作为主要终点，我们将评估RM PBMC、淋巴结和直肠单核细胞（MNC）亚群中与免疫激活和基因表达谱相关的表面和细胞内分子的表达，以及炎症细胞因子和趋化因子的血浆水平；2. 评估治疗对病毒载量、病毒库和作为次要终点的中央记忆CD4+ T细胞保存的影响；3. 评估治疗对所选IGS蛋白水平的影响以及对淋巴结、肠组织和脑切片免疫激活标志物的影响。