Activation of latent HIV using drug-loaded nanoparticles.
Activation of latent HIV using drug-loaded nanoparticles.
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DOI：
10.1371/journal.pone.0018270
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发表时间：
2011-04-05
期刊：
影响因子：
3.7
通讯作者：
Zack JA
中科院分区：
文献类型：
--
作者：
Kovochich M;Marsden MD;Zack JA
目前，抗逆转录病毒治疗只能控制艾滋病病毒复制，并不能完全根除患者体内的病毒。部分原因是在静息 CD4+ T 细胞中建立了潜伏病毒库，即使在 HAART 存在下，该病毒库仍持续存在。据认为，强制激活潜伏感染细胞可以诱导病毒产生，从而使免疫反应能够靶向细胞。有多种分子能够从潜伏期刺激艾滋病毒。然而，没有经过测试的清除策略被证明能够完全消除感染或在治疗停止时防止病毒反弹。因此需要新颖的延迟激活方法。与更传统的药物递送方法相比，纳米颗粒具有多种优势，包括提高药物溶解度、稳定性以及同时将多种不同分子靶向特定细胞或组织类型的能力。在这里，我们描述了一种掺有蛋白激酶 C 激活剂苔藓抑素 2 (LNP-Bry) 的新型脂质纳米颗粒的开发。这些颗粒可以靶向并激活原代人类 CD4+ T 细胞，并刺激体外人类 T 细胞系和离体人源化小鼠模型中潜伏感染细胞的潜伏病毒产生。 HDAC 抑制剂丁酸钠可协同增强这种激活作用。此外，LNP-Bry还可以负载蛋白酶抑制剂奈非那韦（LNP-Bry-Nel），产生既能激活潜伏病毒又能抑制病毒传播的颗粒。总而言之，这些数据证明了纳米技术方法能够提供激活潜伏 HIV 的改进方法，并提供关键的原理验证实验，展示新型输送系统如何增强未来的 HIV 治疗。
Antiretroviral therapy is currently only capable of controlling HIV replication rather than completely eradicating virus from patients. This is due in part to the establishment of a latent virus reservoir in resting CD4+ T cells, which persists even in the presence of HAART. It is thought that forced activation of latently infected cells could induce virus production, allowing targeting of the cell by the immune response. A variety of molecules are able to stimulate HIV from latency. However no tested purging strategy has proven capable of eliminating the infection completely or preventing viral rebound if therapy is stopped. Hence novel latency activation approaches are required. Nanoparticles can offer several advantages over more traditional drug delivery methods, including improved drug solubility, stability, and the ability to simultaneously target multiple different molecules to particular cell or tissue types. Here we describe the development of a novel lipid nanoparticle with the protein kinase C activator bryostatin-2 incorporated (LNP-Bry). These particles can target and activate primary human CD4+ T-cells and stimulate latent virus production from human T-cell lines in vitro and from latently infected cells in a humanized mouse model ex vivo. This activation was synergistically enhanced by the HDAC inhibitor sodium butyrate. Furthermore, LNP-Bry can also be loaded with the protease inhibitor nelfinavir (LNP-Bry-Nel), producing a particle capable of both activating latent virus and inhibiting viral spread. Taken together these data demonstrate the ability of nanotechnological approaches to provide improved methods for activating latent HIV and provide key proof-of-principle experiments showing how novel delivery systems may enhance future HIV therapy.
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