Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation
Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation
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DOI：
10.1172/jci39199
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发表时间：
2009-11-01
影响因子：
15.9
通讯作者：
Siliciano, Robert F.
中科院分区：
文献类型：
--
作者：
Yang, Hung-Chih;Xing, Sifei;Siliciano, Robert F.
治疗HIV-1感染者的高效抗逆转录病毒疗法（HAART）的发展极大地改善了患者的预后，但HAART仍未能治愈感染。静息CD 4（+）T细胞中的潜伏病毒库是病毒根除的主要障碍。消除这种储存库需要重新激活潜伏病毒。然而，通过非特异性T细胞激活来重新激活HIV-1的策略具有临床上不可接受的毒性。我们在这里描述了我们认为是一种新的HIV-1潜伏期体外模型的发展，我们用来寻找可以逆转潜伏期的化合物。用促生存分子Bcl-2转导人原代CD 4（+）T细胞，所产生的细胞表现出重现体内静息CD 4（+）T细胞的静止状态。使用该模型系统，我们筛选了小分子文库，并鉴定了一种重新激活潜伏的HIV-1而不诱导整体T细胞活化的化合物，5-羟基萘-1，4-二酮（5 HN）。与先前描述的潜伏逆转剂不同，5 HN通过ROS和NF-κ B活化潜伏的HIV-1，而不影响活化T细胞的核因子（NFAT）和PKC，表明TCR途径可被分解并用于清除潜伏的病毒。我们的研究扩大了潜伏期逆转疗法的种类，并证明了这种体外模型在寻找根除HIV-1感染的策略方面的实用性。
The development of highly active antiretroviral therapy (HAART) to treat individuals infected with HIV-1 has dramatically improved patient outcomes, but HAART still fails to cure the infection. The latent viral reservoir in resting CD4(+) T cells is a major barrier to virus eradication. Elimination of this reservoir requires reactivation of the latent virus. However, strategies forreactivating HIV-1 through nonspecific T cell activation have clinically unacceptable toxicities. We describe here the development of what we believe to be a novel in vitro model of HIV-1 latency that we used to search for compounds that can reverse latency. Human primary CD4(+) T cells were transduced with the prosurvival molecule Bcl-2, and the resulting cells were shown to recapitulate the quiescent state of resting CD4(+) T cells in vivo. Using this model system, we screened small-molecule libraries and identified a compound that reactivated latent HIV-1 without inducing global T cell activation, 5-hydroxynaphthatene-1,4-dione (5HN). Unlike previously described latency-reversing agents, 5HN activated latent HIV-1 through ROS and NF-kappa B without affecting nuclear factor of activated T cells (NFAT) and PKC, demonstrating that TCR pathways can be dissected and utilized to purge latent virus. Our study expands the number of classes of latency-reversing therapeutics and demonstrates the utility of this in vitro model for finding strategies to eradicate HIV-1 infection.