Flavonoid-based inhibition of cyclin-dependent kinase 9 without concomitant inhibition of histone deacetylases durably reinforces HIV latency.
Flavonoid-based inhibition of cyclin-dependent kinase 9 without concomitant inhibition of histone deacetylases durably reinforces HIV latency.
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DOI：
10.1016/j.bcp.2021.114462
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发表时间：
2021-04
影响因子：
5.8
通讯作者：
Tietjen I
中科院分区：
文献类型：
--
作者：
Schonhofer C;Yi J;Sciorillo A;Andrae-Marobela K;Cochrane A;Harris M;Brumme ZL;Brockman MA;Mounzer K;Hart C;Gyampoh K;Yuan Z;Montaner LJ;Tietjen I
虽然联合抗逆转录病毒疗法 (cART) 可持久抑制 HIV 复制，但病毒仍存在于 CD4+ T 细胞中，这些细胞含有潜在但可自发诱导且具有复制能力的原病毒。灭活这些病毒库的一种策略是使用即使在停药后仍能继续增强艾滋病毒潜伏期的药物。为了识别具有此类特性的新化学先导物，我们研究了一系列天然存在的黄酮（白杨素、芹菜素、木犀草素和木犀草素-7-葡萄糖苷（L7G））和功能相关的细胞周期蛋白依赖性激酶9（CDK9）抑制剂（flavopiridol和atuveciclib），据报道或推测它们可以抑制HIV在HIV病毒中的复制。 体外。我们发现，虽然所有化合物都能抑制体外潜伏期逆转剂诱导的原病毒表达，但只有苷元类黄酮（白杨素、芹菜素、木犀草素、黄吡醇）和 atuveciclib 抑制自发潜伏期逆转，而糖基化黄酮类 L7G 则不然。苷元类黄酮和 atuveciclib（但 L7G 除外）也能抑制 CDK9 和 HIV Tat 蛋白。糖苷配基黄酮类化合物在体外戒断后不会增强 HIV 潜伏期，这与它们抑制 I/II 类组蛋白脱乙酰酶 (HDAC) 的能力相对应，HDAC 是一种成熟的潜伏期逆转机制。相比之下，atuveciclib 和 flavopiridol 几乎没有或没有表现出 HDAC 抑制作用，在体外停药后，潜伏期持续增强，分别持续 9 至 14 天以上。最后，我们发现，flavopiridol 还可以抑制 HIV 捐赠者的 CD4+ T 细胞中自发的离体病毒 RNA 产生。这些结果表明 CDK9 抑制（在没有 HDAC 抑制的情况下）是寻找持久增强 HIV 潜伏期的化合物的潜在有利特性。
While combination antiretroviral therapy (cART) durably suppresses HIV replication, virus persists in CD4+ T-cells that harbor latent but spontaneously inducible and replication-competent provirus. One strategy to inactivate these viral reservoirs involves the use of agents that continue to reinforce HIV latency even after their withdrawal. To identify new chemical leads with such properties, we investigated a series of naturally-occurring flavones (chrysin, apigenin, luteolin, and luteolin-7-glucoside (L7G)) and functionally-related cyclin dependent kinase 9 (CDK9) inhibitors (flavopiridol and atuveciclib) which are reported or presumed to suppress HIV replication in vitro. We found that, while all compounds inhibit provirus expression induced by latency-reversing agents in vitro, only aglycone flavonoids (chrysin, apigenin, luteolin, flavopiridol) and atuveciclib, but not the glycosylated flavonoid L7G, inhibit spontaneous latency reversal. Aglycone flavonoids and atuveciclib, but not L7G, also inhibit CDK9 and the HIV Tat protein. Aglycone flavonoids do not reinforce HIV latency following their in vitro withdrawal, which corresponds with their ability to also inhibit class I/II histone deacetylases (HDAC), a well-established mechanism of latency reversal. In contrast, atuveciclib and flavopiridol, which exhibit little or no HDAC inhibition, continue to reinforce latency for 9 to 14+ days, respectively, following their withdrawal in vitro. Finally, we show that flavopiridol also inhibits spontaneous ex vivo viral RNA production in CD4+ T cells from donors with HIV. These results implicate CDK9 inhibition (in the absence of HDAC inhibition) as a potentially favorable property in the search for compounds that durably reinforce HIV latency.
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