The fact that HIV-1 inside human bodies can perform reverse transcription and integrate resultant DNA into host chromosome remains a challenge in AIDS treatment. “Shock and kill” strategy was proposed to achieve the functional cure, which requested latency reactivating agents (LRAs) to reactivate latent HIV-1 and then extirpate viruses and infected cells with antiviral agents and the immune system. However, there are no feasible LRAs clinically applied. Herein, we examined a synthesized HDAC I inhibitor, CC-4a, in reactivating latent HIV-1 and investigated its mechanisms. Two HIV-1 infected cell models and human PBMCs were used in this study. Flow cytometry, ELISA, luciferase, and RT-PCR assay were used to analyze the expression of viral protein and mRNA. The mechanisms were explored by using cytoplasmic nuclear protein isolation and western blotting assays. CC-4a could successfully reactivate latent HIV-1 at the protein and gene levels with low cytotoxicity. Intriguingly, CC-4a showed the ability to induce apoptosis in HIV-1 infected cell models. CC-4a exerted a synergistic activation effect with prostratin without triggering global T cell activation and inflammatory factor storm. It was further found that CC-4a down-regulated the expressions of CCR5 and CD4. Moreover, CC-4a together with antiviral drugs was proved to antagonize HIV-1 without mutual interference. Finally, the enhanced histone acetylation and activated NF-κB pathway were detected in CC-4a mechanisms. The results suggested that CC-4a activated latent HIV-1 and showed promising clinical applications, demonstrating that CC-4a played a role in HIV-1 eradication in “shock and kill” strategy.

中文翻译：

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新型选择性组蛋白脱乙酰酶 I 抑制剂 CC-4a 通过 NF-κB 通路激活潜在的 HIV-1


HIV-1在人体内可以进行逆转录并将所得DNA整合到宿主染色体中，这一事实仍然是艾滋病治疗中的一个挑战。为了实现功能性治愈，提出了“休克和杀伤”策略，要求潜伏再激活剂（LRAs）重新激活潜伏的HIV-1，然后用抗病毒剂和免疫系统消灭病毒和感染细胞。然而，目前还没有可行的LRA应用于临床。在此，我们检查了合成的 HDAC I 抑制剂 CC-4a 在重新激活潜在 HIV-1 方面的作用并研究了其机制。本研究使用了两种 HIV-1 感染细胞模型和人类 PBMC。采用流式细胞术、ELISA、荧光素酶和RT-PCR检测分析病毒蛋白和mRNA的表达。通过使用细胞质核蛋白分离和蛋白质印迹分析来探索其机制。 CC-4a 可以在蛋白质和基因水平上成功地重新激活潜伏的 HIV-1，且细胞毒性较低。有趣的是，CC-4a 在 HIV-1 感染的细胞模型中表现出诱导细胞凋亡的能力。 CC-4a与前列腺素发挥协同激活作用，而不引发全局T细胞激活和炎症因子风暴。进一步发现CC-4a下调CCR5和CD4的表达。此外，CC-4a与抗病毒药物一起被证明可以拮抗HIV-1，且互不干扰。最后，在 CC-4a 机制中检测到增强的组蛋白乙酰化和激活的 NF-κB 通路。结果表明，CC-4a激活了潜伏的HIV-1，并显示出良好的临床应用前景，证明CC-4a在“休克和杀戮”策略中发挥了消灭HIV-1的作用。