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药性物种之间唯一最显著的差异。免疫激活可由多种机制诱导，包括病毒抗原刺激免疫反应、产生超抗原和/或产生激活的细胞因子和趋化因子。在艾滋病毒感染期间，很可能同时发生一种以上的机制。我们已经证明，HIV和SIV感染调节灵长类APC和T细胞基因的表达，并且至少有一部分在感染者和RM IDC中重新编程的干扰素刺激基因(ISG)在艾滋病抗性物种的APC中不受SIV感染的影响。我们推测，免疫激活的诱导和维持可能依赖于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，并已在体外证明了这一点。P38MAPK在HIV和SIV感染中被激活，是诱导ISG的关键途径，并在体内与HIV和SIV感染在艾滋病易感灵长类动物中产生的一些病理有关。由于p38 MAPK的抑制剂是可用的，目前已在针对其他疾病的人体试验中进行了测试，我们打算评估在针对不同人类疾病的试验中结合ART使用p38抑制剂治疗SIV感染猕猴的效果，该抑制剂已被证明可降低免疫激活。我们的目标是：1在活体内评价PH-797804单独或与ART联用对SIV感染的RM免疫激活的影响。作为主要终点，我们将评估与免疫激活相关的表面和细胞内分子在RM PBMC、淋巴结和直肠单个核细胞(MNC)亚群中的表达和基因表达谱，以及血浆炎症细胞因子和趋化因子的水平；2.评估治疗对作为次要终点的病毒载量、病毒库和中枢记忆CD4+T细胞的保存的影响；3.评估治疗对选定的IGS的蛋白水平以及对淋巴结、肠组织和脑切片中免疫激活标志物的影响。

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.