Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4+ T cell activation and HIV-1 latency reversal
Hybrid nanocarriers incorporating mechanistically distinct drugs for lymphatic CD4+ T cell activation and HIV-1 latency reversal
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DOI：
10.1126/sciadv.aav6322
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发表时间：
2019-03-01
期刊：
影响因子：
13.6
通讯作者：
Woodrow, Kim A.
中科院分区：
文献类型：
--
作者：
Cao, Shijie;Slack, Sarah D.;Woodrow, Kim A.
一种拟议的治愈艾滋病毒的战略使用潜伏期反转剂(LRA)来重新激活潜伏期前病毒，以清除艾滋病毒宿主。已经确定了多种LRA，但还没有一种在体内被证明能有效地缩小储存库的大小。纳米载体可以改善药物的溶解性和安全性，提供持续的药物释放，并同时将多种药物输送到靶组织和细胞，从而解决一些重大挑战。在这里，我们形成了混合纳米载体，结合了物理化学上不同的LRA和靶向淋巴CD4(+)T细胞。我们发现了一种在HIV细胞模型和病毒学抑制患者的CD4(+)T细胞中显示出协同潜伏期逆转和低细胞毒性的LRA组合。此外，我们的靶向纳米载体选择性地激活了非人类灵长类动物外周血单个核细胞以及小鼠淋巴结中的CD4(+)T细胞，并显著降低了局部毒性。这种纳米载体平台可能会为治疗艾滋病毒的抗艾滋病毒药物的输送提供新的解决方案。
A proposed strategy to cure HIV uses latency-reversing agents (LRAs) to reactivate latent proviruses for purging HIV reservoirs. A variety of LRAs have been identified, but none has yet proven effective in reducing the reservoir size in vivo. Nanocarriers could address some major challenges by improving drug solubility and safety, providing sustained drug release, and simultaneously delivering multiple drugs to target tissues and cells. Here, we formulated hybrid nanocarriers that incorporate physicochemically diverse LRAs and target lymphatic CD4(+) T cells. We identified one LRA combination that displayed synergistic latency reversal and low cytotoxicity in a cell model of HIV and in CD4(+) T cells fromvirologically suppressed patients. Furthermore, our targeted nanocarriers selectively activated CD4(+) T cells in nonhuman primate peripheral blood mononuclear cells aswell as inmurine lymph nodes, and substantially reduced local toxicity. This nanocarrier platform may enable new solutions for delivering anti-HIV agents for an HIV cure.