BackgroundCurrent efforts towards HIV-1 eradication focus on the reactivation and elimination of the latent viral reservoir, so-called shock and kill therapy. However, work from several groups indicates that infected cell death following virus reactivation is not guaranteed. Thus, it is imperative to develop strategies to foster specific elimination of cells carrying integrated proviruses. It has been shown that some non-nucleoside reverse transcriptase inhibitors (NNRTIs) including efavirenz can induce premature HIV-1 GagPol dimerization in productively infected cells, resulting in intracellular HIV-1 Protease (PR) activation and a reduction in HIV-1 expressing cells.ResultsHere, we document that NNRTI-induced PR activation triggers apoptotic death of productively infected resting or activated T cells in as little as 2 h via caspase-dependent and independent pathways. Rilpivirine, efavirenz and etravirine were the most potent NNRTIs, whereas nevirapine had almost no effect. NNRTI-induced cell killing was prevented by inhibitors of HIV-1 Protease (PR) activity including indinavir and nelfinavir. HIV-1 transmitter founder viruses induced cell killing similarly to lab-adapted HIV-1 except when NNRTI resistance conferring mutations were present in reverse transcriptase. Mutations in PR that confer PR inhibitor (PI) resistance restore NNRTI-induced killing in the presence of PI. Finally, we show that NNRTIs can rapidly eliminate cells in which latent viruses are stimulated to active expression.ConclusionsThis work supports the notion that select NNRTIs might help promote the elimination of HIV-1 producing cells as an adjuvant during shock and kill therapy.

中文翻译：

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NNRTI 诱导的 HIV-1 蛋白酶介导的细胞毒性在生产性感染和潜伏期逆转期间诱导 CD4 T 细胞快速死亡

背景当前根除 HIV-1 的努力集中在重新激活和消除潜伏病毒库，即所谓的休克和杀灭疗法。然而，来自多个小组的工作表明，不能保证病毒重新激活后感染细胞死亡。因此，必须制定策略以促进特异性消除携带整合前病毒的细胞。已经表明，包括依法韦仑在内的一些非核苷逆转录酶抑制剂 (NNRTIs) 可以在有效感染的细胞中诱导过早的 HIV-1 GagPol 二聚化，导致细胞内 HIV-1 蛋白酶 (PR) 激活和 HIV-1 表达细胞的减少.结果在这里，我们记录了 NNRTI 诱导的 PR 激活通过半胱天冬酶依赖性和独立途径在短短 2 小时内触发有效感染的静息或活化 T 细胞的凋亡死亡。利匹韦林、依法韦仑和依曲韦林是最有效的 NNRTIs，而奈韦拉平几乎没有作用。NNRTI 诱导的细胞杀伤被 HIV-1 蛋白酶 (PR) 活性抑制剂包括茚地那韦和奈非那韦阻止。除了逆转录酶中存在 NNRTI 抗性突变时，HIV-1 递质始祖病毒与实验室适应的 HIV-1 类似地诱导细胞杀伤。在 PI 存在下，赋予 PR 抑制剂 (PI) 抗性的 PR 突变恢复了 NNRTI 诱导的杀伤。最后，我们表明 NNRTIs 可以快速消除潜伏病毒被刺激到活跃表达的细胞。