In vivo suppression of SIV-mediated immune activation

描述（由申请人提供）：免疫激活水平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。在某些物种中，较高的免疫激活水平与HIV和SIV的致病性相关，可能是因为CD4+ T细胞免疫激活的增加会导致免疫激活介导的细胞凋亡增加，同时伴随着CD4+ T细胞的耗竭。免疫激活可以通过多种机制诱导，包括病毒抗原持续刺激免疫反应，和/或产生免疫激活细胞因子和趋化因子。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诱导的细胞途径，导致免疫激活细胞因子和趋化因子的产生，并已在体外证明这是情况。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。我们确定了病毒蛋白Tat如何直接调节导致p38 MAPK通路激活的细胞蛋白。由于没有阻断Tat活性的有效药物存在，p38 MAPK抑制剂可用，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p38抑制剂在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。为了纵向评估体内ph -797804介导的p38 MAPK抑制对四种siv感染RM的免疫激活的影响，通过评估RM PBMC、淋巴结和直肠粘膜活检中与免疫激活相关的基因表达谱和表面分子的表达以及血清炎症细胞因子和趋化因子的水平作为主要终点；2. 评估作为次要终点的治疗对病毒载量、中枢记忆性CD4+ T细胞的保存以及可能对疾病进展的影响。这项工作可以为在临床前和临床试验中测试p38 MAPK抑制剂提供理论依据，并鼓励开发有效的Tat抑制剂。

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.