佛手苷内酯对潜伏HIV的激活效应及其机制研究

The persistence of HIV-1 latent reservoirs is a major barrier of combined antiretroviral therapy (cART) to achieve a complete cure for HIV. The strategy"shock and kill" using HIV latency reversing agents (LRAs) can achieve thefunctional cure of HIV by reactivating the HIV proviruses integrated in the hostgenome and eliminating latent viral reservoirs. Previous literature reported that coumarins can activate latent HIV effectively. This project intends to reveal in depth the activation effect and molecular mechanism of Bergapten on HIV latent infection, and to explore the possibility of Bergapten as new LRAs. The main research contents include: 1) evaluating the ability of Bergapten to activate latent HIV-1 through in vitro latent infection cell model and primary cells of HIV-infected persons; 2) evaluating its cytotoxicity to normal PBMCs and CD4+T cells and the expression of host cell receptors and related factors; 3) evaluating its synergistic effect with cART antiviral drugs and candidate latent infection activating drug LRAs; 4) A series of molecular biological methods were used to elucidate the potential targets of Bergapten in activating latent HIV infection. This project aims to confirm that Bergapten is a novel HIV LRAs, expecting it to eradicate the resevoir of HIV latency and achieving a final functional cure of HIV/AIDS.

HIV潜伏病毒储存库的存在是导致抗逆转录病毒药物无法治愈艾滋病的主要原因。采用“激活并杀灭”的策略，通过活化HIV前病毒，清除潜伏病毒库，有望实现功能性治愈。前期文献报道香豆素类化合物可以有效激活潜伏HIV。本项目拟深入揭示呋喃香豆素佛手苷内酯对HIV潜伏感染的激活效应及其分子机制，并探讨其作为新型潜伏感染激活剂药物的可能性。主要研究内容包括：1）通过体外潜伏感染细胞模型以及HIV感染者原代细胞评价佛手苷内酯激活潜伏HIV-1的能力；2）评估其对正常PBMCs及CD4+T细胞的细胞毒性及对宿主细胞受体及相关因子表达的影响；3）评价其与cART抗病毒药物及候选潜伏感染激活药物LRAs协同效果；4）利用一系列分子生物学手段，深入阐明佛手苷内酯激活HIV潜伏感染的可能作用靶点。本项目旨在确证佛手苷内酯为新型HIV潜伏感染激活剂，期望其清除HIV潜伏感染库，实现HIV功能性治愈。

HIV潜伏病毒储存库的存在是导致抗逆转录病毒药物无法治愈艾滋病的主要原因。采用“激活并杀灭”的策略，通过活化HIV前病毒，清除潜伏病毒库，有望实现功能性治愈。本项目通过以下几个方面对佛手苷内酯进行了研究：1）通过体外潜伏感染细胞模型以及HIV感染者原代细胞，初步评价了其激活能力；2）评价其对PBMCs的毒性、对宿主细胞受体及相关因子表达的影响，初步证实了其安全性；3）对其与cART抗病毒药物及其他激活剂协同效果进行评价，证实了其不影响抗病毒药物的治疗效果；4）探究其激活HIV-1潜伏储存库的作用机制，发现除了NF-KB通路之外，也通过HSF1通路对潜伏感染HIV发挥作用。本课题研究有望为开发出以佛手苷内酯为原创性有效安全的新型HIV 潜伏感染激活剂奠定基础，以期彻底清除HIV潜伏感染库，实现HIV“功能性”治愈的目标！