Epigenetic Suppression of HIV in Myeloid Cells by the BRD4-Selective Small Molecule Modulator ZL0580
Epigenetic Suppression of HIV in Myeloid Cells by the BRD4-Selective Small Molecule Modulator ZL0580
复制标题
DOI：
10.1128/jvi.01880-19
复制
发表时间：
2020-06-01
影响因子：
5.4
通讯作者：
Hu, Haitao
中科院分区：
文献类型：
--
作者：
Alamer, Edrous;Zhong, Chaojie;Hu, Haitao
脑内小胶质细胞和骨髓细胞（血管周围巨噬细胞）是体内重要的HIV储库，尤其是在中枢神经系统（CNS）中。尽管进行了抗逆转录病毒治疗（ART），但这些储库中的低水平持续HIV复制仍然可以检测到，这有助于HIV感染患者的神经炎症和神经系统疾病。需要新的方法来补充ART以抑制CNS储库中的残留HIV复制。我们的研究小组最近发现了一种BRD 4选择性小分子调节剂（ZL 0580），可诱导HIV的表观遗传抑制。在这里，我们研究了这种化合物对人类骨髓细胞中HIV的影响。我们发现，ZL 0580在小胶质细胞（HC 69）和单核细胞系（U1和OM 10.1）中诱导和基础HIV转录均受到有效和持久的抑制。用ZL 0580预处理小胶质细胞使它们对潜伏的HIV再活化更难抵抗，表明ZL 0580对小胶质细胞中的HIV长末端重复序列（LTR）的表观遗传重编程效应。我们还证明，ZL 0580通过在ART治疗期间促进HIV抑制，在人原代单核细胞衍生的巨噬细胞（MDM）中诱导对HIV的抑制作用。在机制上，ZL 0580通过破坏达特与CDK 9的结合来抑制小胶质细胞中的达特反式激活，这是HIV转录延伸的关键过程。高分辨率微球菌核酸酶图谱显示，ZL 0580在HIV LTR处诱导抑制性染色质结构。综上所述，我们的数据表明，ZL 0580代表了一种潜在的方法，可用于与ART结合，以抑制残留的HIV复制和/或潜伏的HIV在CNS水库再激活，从而减少HIV相关neuroninflammation.IMPORTANCE脑驻留小胶质细胞和血管周围巨噬细胞是重要的HIV水库在CNS。持续的病毒复制和潜伏的HIV在CNS中的再激活，即使在ART下，也被认为会发生，导致HIV感染患者的神经炎症和神经系统疾病。关键是要确定新的方法，可以控制残留的艾滋病毒复制和/或潜伏的艾滋病毒再激活这些水库。我们在这里报告，BRD 4选择性小分子调节剂，ZL 0580，诱导有效和持久的抑制人类小胶质细胞和单核细胞系的HIV。使用体外HIV感染，ART治疗的MDM模型，我们表明ZL 0580也诱导对人原代巨噬细胞中HIV的抑制作用。我们的研究的意义在于，它提出了一种潜在的新方法，该方法与ART结合使用，可抑制CNS储库中残留的HIV复制和/或HIV再活化，从而减少HIV感染者的神经炎症和神经系统疾病。
Brain-resident microglia and myeloid cells (perivascular macrophages) are important HIV reservoirs in vivo, especially in the central nervous system (CNS). Despite antiretroviral therapy (ART), low-level persistent HIV replication in these reservoirs remains detectable, which contributes to neuroinflammation and neurological disorders in HIV-infected patients. New approaches complementary to ART to repress residual HIV replication in CNS reservoirs are needed. Our group has recently identified a BRD4-selective small molecule modulator (ZL0580) that induces the epigenetic suppression of HIV. Here, we examined the effects of this compound on HIV in human myeloid cells. We found that ZL0580 induces potent and durable suppression of both induced and basal HIV transcription in microglial cells (HC69) and monocytic cell lines (U1 and OM10.1). Pretreatment of microglia with ZL0580 renders them more refractory to latent HIV reactivation, indicating an epigenetic reprogramming effect of ZL0580 on HIV long terminal repeat (LTR) in microglia. We also demonstrate that ZL0580 induces repressive effect on HIV in human primary monocyte-derived macrophages (MDMs) by promoting HIV suppression during ART treatment. Mechanistically, ZL0580 inhibits Tat transactivation in microglia by disrupting binding of Tat to CDK9, a process key to HIV transcription elongation. High-resolution micrococcal nuclease mapping showed that ZL0580 induces a repressive chromatin structure at the HIV LTR. Taken together, our data suggest that ZL0580 represents a potential approach that could be used in combination with ART to suppress residual HIV replication and/or latent HIV reactivation in CNS reservoirs, thereby reducing HIV-associated neuroinflammation.IMPORTANCE Brain-resident microglia and perivascular macrophages are important HIV reservoirs in the CNS. Persistent viral replication and latent HIV reactivation in the CNS, even under ART, are believed to occur, causing neuroinflammation and neurological disorders in HIV-infected patients. It is critical to identify new approaches that can control residual HIV replication and/or latent HIV reactivation in these reservoirs. We here report that the BRD4-selective small molecule modulator, ZL0580, induces potent and durable suppression of HIV in human microglial and monocytic cell lines. Using an in vitro HIV-infected, ART-treated MDM model, we show that ZL0580 also induces suppressive effect on HIV in human primary macrophages. The significance of our research is that it suggests a potential new approach that has utility in combination with ART to suppress residual HIV replication and/or HIV reactivation in CNS reservoirs, thereby reducing neuroinflammation and neurological disorders in HIV-infected individuals.