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首页> 外文期刊>Molecular and Cellular Biology >A Minor Subset of Super Elongation Complexes Plays a Predominant Role in Reversing HIV-1 Latency
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A Minor Subset of Super Elongation Complexes Plays a Predominant Role in Reversing HIV-1 Latency

机译：超延伸复合物的小亚集在逆转HIV-1潜伏期中起主要作用

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Promoter-proximal pausing by RNA polymerase II (Pol II) is a key rate-limiting step in HIV-1 transcription and latency reversal. The viral Tat protein recruits human super elongation complexes (SECs) to paused Pol II to overcome this restriction. Despite the recent progress in understanding the functions of different subsets of SECs in controlling cellular and Tat-activated HIV transcription, little is known about the SEC subtypes that help reverse viral latency in CD4+ T cells. Here, we used the CRISPR-Cas9 genome-editing tool to knock out the gene encoding the SEC subunit ELL2, AFF1, or AFF4 in Jurkat/2D10 cells, a well-characterized HIV-1 latency model. Depletion of these proteins drastically reduced spontaneous and drug-induced latency reversal by suppressing HIV-1 transcriptional elongation. Surprisingly, a low-abundance subset of SECs containing ELL2 and AFF1 was found to play a predominant role in cooperating with Tat to reverse latency. By increasing the cellular level/activity of these Tat-friendly SECs, we could potently activate latent HIV-1 without using any drugs. These results implicate the ELL2/AFF1-SECs as an important target in the future design of a combinatorial therapeutic approach to purge latent HIV-1.
机译：RNA聚合酶II（Pol II）引起的启动子近端暂停是HIV-1转录和潜伏期逆转的关键速率限制步骤。病毒Tat蛋白募集了人类超伸长复合物（SEC）来暂停Pol II，以克服这一限制。尽管最近在理解SEC的不同子集在控制细胞和Tat激活的HIV转录中的功能方面取得了进展，但对帮助逆转CD4 + T细胞中病毒潜伏期的SEC亚型知之甚少。在这里，我们使用了CRISPR-Cas9基因组编辑工具敲除Jurkat / 2D10细胞中的SEC亚基ELL2，AFF1或AFF4的编码基因，该细胞是特征明确的HIV-1潜伏期模型。这些蛋白质的消耗通过抑制HIV-1转录延伸而大大减少了自发和药物诱导的潜伏期逆转。令人惊讶的是，发现含有ELL2和AFF1的SEC的低丰度子集在与Tat合作扭转潜伏期方面起着主要作用。通过提高这些对Tat友好的SEC的细胞水平/活性，我们可以有效地激活潜在的HIV-1，而无需使用任何药物。这些结果表明，ELL2 / AFF1-SECs是未来设计清除潜在HIV-1的组合治疗方法的重要目标。

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