β-catenin regulates HIV latency and modulates HIV reactivation.
β-catenin regulates HIV latency and modulates HIV reactivation.
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DOI：
10.1371/journal.ppat.1010354
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发表时间：
2022-03
期刊：
影响因子：
6.7
通讯作者：
Al-Harthi L
中科院分区：
文献类型：
--
作者：
Barbian HJ;Seaton MS;Narasipura SD;Wallace J;Rajan R;Sha BE;Al-Harthi L
潜伏期是治愈HIV的主要障碍，治疗策略的目的是诱导或防止病毒再激活。虽然这些策略显示出了希望，但它们只成功地调节了一小部分潜伏HIV病毒库的潜伏期，这表明控制HIV病毒潜伏期的机制尚未完全了解，全面的潜伏期调节将需要针对多种潜伏期维持途径。我们在这里表明，转录共激活因子和典型Wnt信号的中心介质β-catenin通过TCF-4 LTR结合位点抑制CD4+ T细胞中的HIV转录。此外，我们发现抑制β-catenin通路在HIV潜伏期的原代中医细胞模型、来自cart控制的HIV供体的原代细胞和CD4+潜伏细胞系中重新激活HIV。在这些模型中，β-catenin的抑制或激活也分别增强或抑制了几种HIV潜伏期逆转药物的活性，并且β-catenin与所测试的每种LRA类具有显著的协同作用。总之，我们发现β-catenin是体外和体外HIV潜伏期的一种新的调节因子，增加了新的治疗靶点，可能在HIV治愈工作中综合调节HIV潜伏期。尽管经过了30多年的研究，艾滋病毒仍无法治愈。艾滋病毒的治愈将依赖于了解调节艾滋病毒潜伏期的细胞途径，这可以用于治疗策略。我们在这里首次报道了转录共激活剂β-catenin在HIV潜伏期的主要靶点CD4+ T细胞群中调节HIV潜伏期。我们还表明，它的操作可以反应或抑制HIV单独或与已知的HIV潜伏期调节剂组合。总之，我们的研究结果将β-catenin归类为HIV潜伏期的调节因子，在治疗策略中具有重要应用。
Latency is the main obstacle towards an HIV cure, with cure strategies aiming to either elicit or prevent viral reactivation. While these strategies have shown promise, they have only succeeded in modulating latency in a fraction of the latent HIV reservoir, suggesting that the mechanisms controlling HIV latency are not completely understood, and that comprehensive latency modulation will require targeting of multiple latency maintenance pathways. We show here that the transcriptional co-activator and the central mediator of canonical Wnt signaling, β-catenin, inhibits HIV transcription in CD4+ T cells via TCF-4 LTR binding sites. Further, we show that inhibiting the β-catenin pathway reactivates HIV in a primary TCM cell model of HIV latency, primary cells from cART-controlled HIV donors, and in CD4+ latent cell lines. β-catenin inhibition or activation also enhanced or inhibited the activity of several classes of HIV latency reversing agents, respectively, in these models, with significant synergy of β-catenin and each LRA class tested. In sum, we identify β-catenin as a novel regulator of HIV latency in vitro and ex vivo, adding new therapeutic targets that may be combined for comprehensive HIV latency modulation in HIV cure efforts. There is no cure for HIV despite over 30 years of research. An HIV cure will rely on understanding cellular pathways that regulate HIV latency, which can be exploited for cure strategies. We report here for the first time that transcriptional co-activator β-catenin regulates HIV latency in the primary target for HIV latency, the CD4+ T cell population. We also show that its manipulation can reactive or repress HIV alone or in combination with known modulators of HIV latency. Together, our findings classify β-catenin as a regulator of HIV latency with significant applications to cure strategies.
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