Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication
Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication
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DOI：
10.1074/jbc.ra118.002353
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发表时间：
2018-04-20
影响因子：
4.8
通讯作者：
Spector, Stephen A.
中科院分区：
文献类型：
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作者：
Campbell, Grant R.;Bruckman, Rachel S.;Spector, Stephen A.
在这项研究中，我们研究了双重磷脂酰肌醇3-激酶/雷帕霉素（PI 3 K/MTOR）抑制剂dactolisib（NVP-BEZ 235），PI 3 K/MTOR/含溴结构域蛋白4（BRD 4）抑制剂SF 2523，以及bromodomain和额外末端结构域抑制剂JQ 1对人类免疫缺陷病毒1型（HIV）原代巨噬细胞的生产性感染的影响。这些抑制剂没有改变巨噬细胞对HIV感染的初始易感性。然而，dactolisib、JQ 1和SF 2523均通过自噬降解细胞内HIV，以剂量依赖性方式降低巨噬细胞中的HIV复制。用dactolisib、JQ 1或SF 2523处理的巨噬细胞显示出LC 3B脂化与SQSTM 1降解的结合增加，而不诱导细胞死亡增加。LC 3B-II水平在胃酶抑素A存在下进一步增加，表明这些抑制剂诱导自噬通量。针对ATG 5和ATG 7的RNA干扰以及自噬体-溶酶体融合和溶酶体水解酶的药理学抑制剂都阻断了对HIV的抑制。因此，我们证明了PI 3 K/MTOR和PI 3 K/MTOR/BRD 4抑制剂抑制HIV的机制需要自噬体的形成，以及它们随后成熟为自溶酶体。这些数据提供了进一步的证据，支持自噬在控制HIV感染中的作用，并为这类药物在HIV治疗中的应用开辟了新的途径。
In this study, we investigated the effects of the dual phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/MTOR) inhibitor dactolisib (NVP-BEZ235), the PI3K/MTOR/bromodomain-containing protein 4 (BRD4) inhibitor SF2523, and the bromodomain and extra terminal domain inhibitor JQ1 on the productive infection of primary macrophages with human immunodeficiency type-1 (HIV). These inhibitors did not alter the initial susceptibility of macrophages to HIV infection. However, dactolisib, JQ1, and SF2523 all decreased HIV replication in macrophages in a dose-dependent manner via degradation of intracellular HIV through autophagy. Macrophages treated with dactolisib, JQ1, or SF2523 displayed an increase in LC3B lipidation combined with SQSTM1 degradation without inducing increased cell death. LC3B-II levels were further increased in the presence of pepstatin A suggesting that these inhibitors induce autophagic flux. RNA interference for ATG5 and ATG7 and pharmacological inhibitors of autophagosome- lysosome fusion and of lysosomal hydrolases all blocked the inhibition of HIV. Thus, we demonstrate that the mechanism of PI3K/MTOR and PI3K/MTOR/BRD4 inhibitor suppression of HIV requires the formation of autophagosomes, as well as their subsequent maturation into autolysosomes. These data provide further evidence in support of a role for autophagy in the control of HIV infection and open new avenues for the use of this class of drugs in HIV therapy.