Role of p38 MAPK activation in AIDS pathogenesis

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物种和抗性物种之间最显著的差异。免疫活化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HIV感染过程中，很可能有一种以上的机制同时发生。我们已经表明，HIV和SIV感染调节灵长类APC和T细胞基因表达，并且在感染的人和RM iDC中重编程的IFN刺激基因（ISG）的至少一个子集在AIDS抗性物种的APC中不受SIV感染的影响。我们假设免疫激活的诱导和维持可能依赖于HIV或SIV对导致免疫激活细胞因子和趋化因子产生的细胞途径的诱导，并且已经表明这是体外的情况。已报道在HIV和SIV感染中被激活的p38 MAPK是诱导ISG的途径中的关键，并且在体内与由HIV和SIV感染在AIDS易感灵长类动物中产生的一些病理学相关。由于p38 MAPK的抑制剂是可用的，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，该抑制剂已被证明在与ART结合的不同人类疾病的试验中减少免疫激活。我们的目标是：1以在体内评价PH-797804单独或添加到ART中对SIV感染的RM中的免疫活化的影响。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）亚群中的免疫活化和基因表达谱相关的表面和细胞内分子的表达，以及炎性细胞因子和趋化因子的血浆水平;评估治疗对病毒载量、病毒储库和中央记忆CD 4 + T细胞的保存的影响作为次要终点; 3.评价给药对选定IGS蛋白水平以及对淋巴结、肠组织和脑切片中免疫活化标志物的影响。

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.