基于非人灵长类动物模型研究老年艾滋病免疫衰老机制及治疗策略

The elderly people have become a new population at high risk for HIV infection and the elderly HIV/AIDS patients are increasing dramatically in recent years. However, despite successful viral suppression by HAART, elderly HIV+ patients still have a poor clinical outcome. There are numerous evidences that immunosenescence contributes to the progression of age-related diseases and HIV infection profoundly. Thus if we want to heal the elderly AIDS, the key here may be finding new therapeutic strategies to delay the development of immunosenescence. As lacking appreciate animal models, immunosenescence and pathogenesis within elderly AIDS are still not fully tested. While the effective treatment for elderly HIV+ patients is difficult to study. Our previous studies revealed that SIV-infected aged Chinese rhesus macaques suffer high risk of AIDS development in early infection phase and the severe aging of their immune system accelerates disease progression notably. Based on previous work, in this studies we will establish the elderly AIDS animal model by infecting aged Chinese rhesus macaques with SIVmac239 and evaluate their alterations in virology, immunology and pathology during chronic infection to find their characteristics of disease progression and immunosenescence. We will further analyze the levels of viral replication, antiviral immune response, transcriptome, apoptosis, microbial translocation, immune activation and inflammation and find the mechanisms for their effects on immunosenescence and disease progression in elderly AIDS. In order to explore the therapeutic strategies for elderly AIDS, we will finally chose the most proper drugs assisted by HAART to reverse the immunosenescence and restore the immune function in these SIV-infected aged macaques. This work will contribute to researches on the disease characteristics and the pathogenesis of immunosenescence in elderly AIDS and provide scientific evidences for clinical treatment.

中老年人已成为新的HIV感染高危人群，感染者和艾滋病患者人数迅速上升，老年艾滋病患者抗病毒治疗效果不理想。免疫衰老在老年疾病和艾滋病发展中起重要作用，延缓免疫衰老是治疗老年艾滋病的关键。缺乏合适的动物模型限制了老年艾滋病免疫衰老、发病机制和治疗策略研究。我们前期研究发现老年中国猕猴在SIV感染早期就已表现出高度的AIDS进展风险，严重的免疫衰老特征显著加速了疾病进程。本项目拟在前期研究基础上：建立艾滋病老年猕猴模型；研究老年中国猕猴慢性SIVmac239感染过程中的病毒学、免疫学和病理学变化，确定其免疫衰老和发病特征；研究病毒复制、抗病毒免疫反应、转录组、细胞凋亡、微生物移位、免疫活化和炎症等影响免疫衰老及在老年艾滋病中的作用机制；在HAART联合辅助治疗药物干预下，探索逆转免疫衰老和重建免疫功能的治疗策略。本研究将有助于阐明老年艾滋病的发病特征与免疫衰老机制，为临床治疗提供科学依据。

中老年人已成为新的HIV感染高危人群，大于50岁的HIV感染者和艾滋病患者人数迅速上升，然而老年艾滋病患者抗病毒治疗效果不理想。免疫衰老在老年疾病和艾滋病发展中起重要作用，延缓免疫衰老是治疗老年艾滋病的关键。缺乏合适的动物模型限制了老年艾滋病免疫衰老、发病机制和治疗策略研究。本项目建立艾滋病老年猕猴模型；研究老年中国猕猴慢性SIVmac239感染过程中的病毒学、免疫学和病理学变化，确定其免疫衰老和发病特征；研究病毒复制、抗病毒免疫反应、免疫活化和炎症等影响免疫衰老及在老年艾滋病中的作用机制；探索逆转免疫衰老和重建免疫功能的治疗策略。实验结果表明我们建立的老年中国猕猴发病特征非常典型，可作为良好的老年艾滋病模型动物，用以老年艾滋病的发病机制和治疗策略研究。通过对此模型的研究，我们发现T细胞和B细胞的免疫衰老，以及强烈的一型干扰素反应是老年艾滋病发病更快更严重的关键因素；CXCR3+MX1+细胞累积预示了老年艾滋病的快速进展，作为老年艾滋病进展的生物标记物有助于发现针对老年艾滋病的特效药和疗法；DNA结合抑制因子2（Inhibitor Of DNA Binding，ID2）信号通路是老年艾滋病的治疗靶点，其抑制药物匹格列酮是一类噻唑烷二酮类化合物，用于降血糖抗动脉粥样硬化、改善血压、抗炎和抗肿瘤的作用，有用于老年艾滋病治疗的潜力。本研究从建立动物模型到机制研究，再到探索生物标记物和靶向药物，循序渐进地阐明了老年艾滋病的发病特征与免疫衰老机制，也为老年艾滋病的临床治疗提供科学依据。

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