基于老年猕猴AIDS模型研究滤泡CXCR5+CD8+T细胞的免疫衰老机制及功能重建

The research for AIDS treatment has already made considerable progress in recent years. However, how to clean out the entire HIV virus from AIDS patients is still an insolvable problem. Numerous evidences show that one of the important inducements for AIDS pathogenesis is that cytotoxic lymphocytes (CTL) could not effectively clear the HIV virus in the follicles of secondary lymphoid tissues. CXCR5+CD8+ T cells were discovered recently and defined as a subset of CTL residing in the follicle with the potency of clearing HIV virus reservoir. However, CXCR5+CD8+ T cells are still unable to clear the virus reservoir entirely. We consider that immunosenescence induced by HIV infection is the key reason for this phenomenon. But this theory needs to be fully tested. .Our previous work demonstrated that SIV-infected aged Chinese resus macaque characterized by the severe immunosenescence is a favourable animal model for the research of interactions between HIV infection and immunosenescence. Based on the elderly AIDS model, we will further study the influence of immunosenescence on the phenotype, function, distribution, development and signal regulation of CXCR5+CD8+ T cells and the mechanisms within the procress of immunosenescence acting on the anti-viral activity of CXCR5+CD8+ T cells. Then we will explore the methods to restore the function of clearing HIV virus reservoir from CXCR5+CD8+ T cells through appropriate HAART and adjuvant treatment. This research will contribute to the understanding of functional characteristics, immunosenescence mechanisms and functional restoration of CXCR5+CD8+ T cells and provide the scientific basis and theoretical references for the clinical application of CXCR5+CD8+ T cells.

近年来艾滋病的治疗已取得重大进展，但如何完全清除病毒依然是难点问题。研究表明细胞毒性淋巴细胞CTL无法在B细胞滤泡有效清除病毒库是AIDS发病的重要原因之一。CXCR5+CD8+T细胞是近期发现的滤泡驻留CTL，具有清除HIV病毒库的潜能。HIV感染导致的免疫衰老可能是CXCR5+CD8+T细胞无法完全清除病毒库的关键原因，但其中机制尚不明确。我们前期工作发现老年猕猴AIDS模型有严重的免疫衰老特征，是研究HIV感染与免疫衰老相互作用的良好模型。本项目拟应用该模型：研究CXCR5+CD8+T细胞在免疫衰老影响下的表型、功能、分布、发育和信号调节特征和免疫衰老作用机制；应用HAART以及辅助治疗药物进行干预，探索重建滤泡内病毒特异性CXCR5+CD8+T细胞病毒库清除能力的方法。本研究将有助于阐明CXCR5+CD8+T细胞的功能特征、免疫衰老机制及功能重建，为临床应用提供科学依据和理论支持。

滤泡CD8+T细胞是近期发现的滤泡驻留CTL，具有清除HIV病毒库的能力，有用于AIDS细胞疗法的潜能。老年AIDS病人的疾病进展更快并且预后不佳，这可能与滤泡CD8+T细胞抗病毒功能减弱有关。我们猜测免疫衰老可能是导致滤泡CD8+T细胞不能完全清除病毒库的关键原因，需要进一步研究。本项目对比老年与青年AIDS猕猴模型，研究滤泡CD8+细胞在免疫衰老影响下的表型、功能、分布、发育和信号调节特征及免疫衰老作用机制；应用HAART以及辅助治疗药物进行干预，探索如何克服免疫衰老以增强滤泡内病毒特异性滤泡CD8+T细胞清除病毒库的功能。我们发现在病毒优先复制的淋巴滤泡区域，老年猕猴比年轻猕猴表现出更严重的病毒感染和免疫病理学特征。此外老年猕猴淋巴滤泡中大量浸润的滤泡CD8+T细胞没有发挥积极的抗病毒作用，反而由于促炎环境诱导的STAT3高度激活增强了免疫紊乱。这表明衰老对SIV感染具有深远的影响，在次级淋巴组织中引起过度炎症和STAT3激活，引发滤泡CD8+T细胞的过度增殖和功能障碍。因此我们在制定靶向滤泡CD8+T细胞治疗HIV感染的策略时，应充分考虑衰老对治疗效果的影响。

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