Combination antiretroviral therapy (cART) effectively suppresses HIV-1 replication and enables HIV‑infected individuals to live long, productive lives. However, the persistence of HIV-1 reservoirs of both T and myeloid cells with latent or low-replicating HIV-1 in patients under cART makes HIV-1 infection an incurable disease. Recent studies have focused on the development of strategies to activate and purge these reservoirs. Bromodomain and extraterminal domain proteins (BETs) are epigenetic readers involved in modulating gene expression. Several bromodomain inhibitors (BETi) are reported to activate viral transcription in vitro in HIV-1 latency cell lines in a P-TEFb (CDK9/cyclin T1)-dependent manner. Little is known about BETi efficacy in activating HIV-1 reservoir cells under cART in vivo Here we report that a BETi (I-BET151) efficiently activated HIV-1 reservoirs under effective cART in humanized mice in vivo Interestingly, I-BET151 during suppressive cART in vivo activated HIV-1 gene expression only in monocytic cells and not in CD4+ T cells. We further demonstrate that BETi preferentially enhanced HIV-1 gene expression in monocytic cells rather than in T cells and that whereas CDK9 was involved in activating HIV-1 by I-BET151 in both monocytic and T cells, CDK2 enhanced HIV-1 transcription in monocytic cells but inhibited it in T cells. Our findings reveal a role for CDK2 in differential modulation of HIV-1 gene expression in myeloid cells and in T cells and provide a novel strategy to reactivate monocytic reservoirs with BETi during cART.IMPORTANCE Bromodomain inhibitors have been reported to activate HIV-1 transcription in vitro, but their effect on activation of HIV-1 reservoirs during cART in vivo is unclear. We found that BETi (I-BET151) treatment reactivated HIV-1 gene expression in humanized mice during suppressive cART. Interestingly, I-BET151 preferentially reactivated HIV-1 gene expression in monocytic cells, but not in CD4 T cells, in cART-treated mice. Furthermore, I-BET151 significantly increased HIV-1 transcription in monocytic cells, but not in HIV-1-infected CD4 T cells, via CDK2-dependent mechanisms. Our findings suggest that BETi can preferentially activate monocytic HIV-1 reservoir cells and that a combination of reservoir activation agents targeting different cell types and pathways is needed to achieve reactivation of different HIV-1 reservoir cells during cART.

中文翻译：

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抗逆转录病毒疗法下人源化小鼠单核细胞中的一个溴结构域抑制剂对HIV-1的特异性体内激活。

联合抗逆转录病毒疗法（cART）有效抑制HIV-1复制，并使感染了HIV的个体能够长寿，多产。然而，在接受cART的患者中，T细胞和髓样细胞的HIV-1储库的持续存在以及潜在的或低复制的HIV-1使得HIV-1感染成为无法治愈的疾病。最近的研究集中在开发激活和清除这些储层的策略上。溴结构域和末端外结构域蛋白（BETs）是参与调控基因表达的表观遗传阅读器。据报道，几种溴结构域抑制剂（BETi）以P-TEFb（CDK9 / cyclin T1）依赖的方式在HIV-1潜伏期细胞系中激活病毒转录。关于BETi在体内激活cART下激活HIV-1储库细胞的功效知之甚少我们在此报告，BETi（I-BET151）在体内人源化小鼠体内在有效cART下有效激活了HIV-1储库。有趣的是，在抑制性cART期间，I-BET151体内激活的HIV-1基因表达仅在单核细胞而不在CD4 + T细胞中。我们进一步证明，BETi优先增强单核细胞而不是T细胞中的HIV-1基因表达，而CDK9参与通过I-BET151在单核细胞和T细胞中激活HIV-1，而CDK2增强了单核细胞中HIV-1的转录。细胞，但在T细胞中抑制它。我们的发现揭示了CDK2在髓样细胞和T细胞中HIV-1基因表达的差异调节中的作用，并提供了在cART期间用BETi激活单核细胞储库的新策略。重要信息据报道，溴结构域抑制剂在体外可激活HIV-1转录，但在体内cART期间它们对HIV-1贮库的激活作用尚不清楚。我们发现BETi（I-BET151）治疗在抑制性cART过程中重新激活了人源化小鼠中的HIV-1基因表达。有趣的是，在经cART处理的小鼠中，I-BET151优先激活了单核细胞而不是CD4 T细胞中HIV-1基因的表达。此外，I-BET151通过CDK2依赖性机制显着增加了单核细胞中的HIV-1转录，但未感染HIV-1的CD4 T细胞。我们的发现表明，BETi可以优先激活单核HIV-1储库细胞，并且需要在cART期间结合靶向不同细胞类型和途径的储库活化剂来实现不同HIV-1储库细胞的再活化。