In vivo suppression of SIV-mediated immune activation

体内抑制 SIV 介导的免疫激活

基本信息

批准号：
8717584
负责人：
ANNA ALDOVINI
金额：
$ 21.67万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-08 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8717584
关键词：
Acquired Immunodeficiency Syndrome Adverse effects Affect Animals Antigen-Presenting Cells Apoptosis Biological Preservation Biopsy CD4 Positive T Lymphocytes Cause of Death Cell surface Cells Cercocebus atys Cercopithecus pygerythrus Clinical Trials Data Dendritic Cells Development Disease Disease Progression Euthanasia Freezing Gene Activation Gene Expression Genes Goals HIV HIV Infections HIV-1 HLA-DR Antigens Human Immune response In Vitro Individual Infection Inflammation Inflammatory Interferons Interruption Intervention Investigation Kinetics Laboratories Lead Light Link MAP Kinase Gene MAPK14 gene Macaca Macaca mulatta Maintenance Maps Mediating Methods Mitogen-Activated Protein Kinase Inhibitor Molecular Profiling Mucous Membrane Outcome Pathogenicity Pathology Pathway interactions Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pilot Projects Play Population Primates Production Protein Inhibition Proteins RNA Interference Reporting Resistance Role Route SIV Safety Sampling Serum Serum Markers Superantigens Surface T-Cell Depletion T-Lymphocyte Testing Time Viral Antigens Viral Load result Viral Proteins Viremia Virus Virus Diseases Work chemokine cytokine drug development human disease immune activation in vivo inhibitor/antagonist lymph nodes macrophage memory CD4 T lymphocyte nonhuman primate preclinical study public health relevance rectal research study response transcription factor treatment effect

项目摘要

DESCRIPTION (provided by applicant): Differences in levels of immunoactivation have been identified as the single more significant difference between AIDS susceptible and resistant species. Higher levels of immunoactivation correlate with HIV and SIV pathogenicity in certain species, possibly because increased CD4+ T cell immunoactivation would result in increased immunoactivation-mediated apoptosis, accompanied by CD4+ T cell depletion. Immunoactivation can be induced by a variety of mechanisms, including persistent stimulation of immune responses by viral antigens, and/or production of immunoactivating cytokines and chemokines. 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 had 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. We identified how the viral protein Tat directly modulates cellular proteins that lead to the activation of the p38 MAPK pathway. As no effective drugs that block Tat activity exist and 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. Our goal is to 1. To evaluate longitudinally the impact that in vivo PH-797804-mediated inhibition of p38 MAPK has on immune activation in four SIV-infected RM by evaluating as primary end points the gene expression profiles and expression of surface molecules linked to immune activation in RM PBMC, lymph node and rectal mucosa biopsies and the serum levels of inflammatory cytokines and chemokines; 2. to evaluate as secondary end points the effect that the treatment has on viral loads, preservation of central memory CD4+ T cells, and possibly on disease progression. This work could provide the rationale for testing p38 MAPK inhibitors in preclinical and clinical trials and for encouraging the development of effective Tat inhibitors.

描述（由申请人提供）：免疫激活水平的差异已被确定为易感和抗性物种之间更明显的差异。在某些物种中，较高水平的免疫激活与HIV和SIV致病性相关，这可能是因为CD4+ T细胞免疫激活增加会导致免疫活化介导的凋亡增加，并伴有CD4+ T细胞耗竭。可以通过多种机制诱导免疫活化，包括病毒抗原对免疫反应的持续刺激和/或产生免疫激活的细胞因子和趋化因子。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HIV或SIV的诱导，导致细胞因子和趋化因子的产生，并表明在体外是这种情况。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。我们确定了病毒蛋白TAT如何直接调节导致P38 MAPK途径激活的细胞蛋白。由于没有有效的阻断TAT活性的有效药物，并且目前可以在人类试验中针对其他疾病进行p38 MAPK的抑制剂，因此我们打算评估使用P38抑制剂治疗SIV感染的猕猴的影响，该抑制剂已证明在不同人类疾病的试验中降低免疫活性。我们的目标是1。纵向评估体内PH-797804介导的抑制p38 MAPK对四个SIV感染RM的免疫激活的抑制，通过评估基因表达谱和与RM PBMC和RM PBMC的免疫激活相关的基因表达和表面表达，lum pbmc和lum pbmc，lum pbmc和recties mmph node m m m，细胞因子和趋化因子； 2。作为次要端的评估，该治疗对病毒负荷的影响，保存中央记忆CD4+ T细胞以及可能对疾病进展的影响。这项工作可以为临床前和临床试验中测试p38 MAPK抑制剂的基本原理，并鼓励开发有效的TAT抑制剂。