Sequential treatment with 5-aza-2'-deoxycytidine and deacetylase inhibitors reactivates HIV-1.
Sequential treatment with 5-aza-2'-deoxycytidine and deacetylase inhibitors reactivates HIV-1.
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DOI：
10.15252/emmm.201505557
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发表时间：
2016-02-01
影响因子：
11.1
通讯作者：
Van Lint C
中科院分区：
文献类型：
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作者：
Bouchat S;Delacourt N;Kula A;Darcis G;Van Driessche B;Corazza F;Gatot JS;Melard A;Vanhulle C;Kabeya K;Pardons M;Avettand-Fenoel V;Clumeck N;De Wit S;Rohr O;Rouzioux C;Van Lint C
已提出重新激活潜伏感染细胞中的 HIV 基因表达以及有效的 cART 作为一种辅助疗法，旨在消除/减少病毒库大小。使用脱乙酰酶抑制剂 (HDACIs) 的 HIV 临床试验结果对单独使用这些潜伏期逆转剂 (LRAs) 的效率提出了质疑，并强调需要评估其他 LRA 与 HDACIs 的组合。在这里，我们评估了去甲基化剂 (5-AzadC) 与临床可耐受的 HDACIs 联合使用，首先在体外，然后在体外重新激活 HIV-1 潜伏期的治疗潜力。我们表明，在体外和离体试验中，5-AzadC 和 HDACIs 序贯治疗比相应的同时治疗更有效。有趣的是，只有两种连续 LRA 组合治疗测试能够以比单独使用药物更高的方式诱导 HIV-1 颗粒恢复，并且浓度低于人类可耐受的血浆浓度。总而言之，我们的数据揭示了使用 5-AzadC 与 HDACI 组合的益处，并且首次揭示了 LRA 组合治疗时间表以重新激活 HIV 的重要性。
Reactivation of HIV gene expression in latently infected cells together with an efficient cART has been proposed as an adjuvant therapy aimed at eliminating/decreasing the reservoir size. Results from HIV clinical trials using deacetylase inhibitors (HDACIs) question the efficiency of these latency‐reversing agents (LRAs) used alone and underline the need to evaluate other LRAs in combination with HDACIs. Here, we evaluated the therapeutic potential of a demethylating agent (5‐AzadC) in combination with clinically tolerable HDACIs in reactivating HIV‐1 from latency first in vitro and next ex vivo. We showed that a sequential treatment with 5‐AzadC and HDACIs was more effective than the corresponding simultaneous treatment both in vitro and ex vivo. Interestingly, only two of the sequential LRA combinatory treatments tested induced HIV‐1 particle recovery in a higher manner than the drugs alone ex vivo and at concentrations lower than the human tolerable plasmatic concentrations. Taken together, our data reveal the benefit of using combinations of 5‐AzadC with an HDACI and, for the first time, the importance of treatment time schedule for LRA combinations in order to reactivate HIV.