In vivo suppression of SIV-mediated immune activation

描述（由申请人提供）：免疫活化水平的差异已被确定为艾滋病易感物种和抗性物种之间的单一更显著差异。在某些物种中，较高水平的免疫活化与HIV和SIV致病性相关，这可能是因为增加的CD 4 + T细胞免疫活化将导致免疫活化介导的细胞凋亡增加，伴随着CD 4 + T细胞耗竭。免疫活化可以通过多种机制诱导，包括通过病毒抗原持续刺激免疫应答，和/或产生免疫活化细胞因子和趋化因子。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。我们确定了病毒蛋白达特如何直接调节导致p38 MAPK通路激活的细胞蛋白。由于没有有效的药物，阻止达特活动存在和抑制剂的p38 MAPK是可用的，目前在人体试验中测试的其他疾病，我们打算评估的影响，治疗SIV感染的猕猴与p38抑制剂，已被证明可以减少免疫激活在不同的人类疾病的试验。我们的目标是1。通过评估RM PBMC、淋巴结和直肠粘膜活检中与免疫活化相关的表面分子的表达和基因表达谱以及炎性细胞因子和趋化因子的血清水平作为主要终点，纵向评估体内PH-797804介导的p38 MAPK抑制对四种SIV感染的RM中免疫活化的影响; 2.作为次要终点，评估治疗对病毒载量、中央记忆性CD 4 + T细胞的保留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抑制剂以及鼓励开发有效的达特抑制剂提供理论基础。

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.