Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators
Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators
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DOI：
10.1128/jvi.01194-19
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发表时间：
2019-11-01
影响因子：
5.4
通讯作者：
Hiscott, John
中科院分区：
文献类型：
--
作者：
Palermo, Enrico;Acchioni, Chiara;Hiscott, John
人类免疫缺陷病毒（HIV）通过整合到宿主基因组中而建立潜伏期的 T 细胞储存库的存在，是治疗 HIV 的主要障碍，并促使人们制定旨在从潜伏感染细胞中根除 HIV 的策略。 “电击杀灭”策略是消除病毒库最常用的方法之一。尽管几种潜伏期逆转剂（LRA）已显示出有希望的重新激活活性，但它们未能消除细胞储存库。在这项研究中，我们基于先天免疫刺激和表观遗传重编程的结合，评估了一种新的免疫系统介导的清除艾滋病毒储存库的方法。 STING 激动剂 cGAMP（环 GMP-AMP）与 FDA 批准的组蛋白脱乙酰酶抑制剂 resminostat 的组合可显着增加体外 HIV 感染细胞中 HIV 前病毒的再激活和特异性凋亡。在CD4（+）中央记忆T（T-CM）细胞（一种潜伏期的原代细胞模型）中也观察到携带HIV的细胞比例和HIV DNA总量的减少，其中resminostat单独或与cGAMP一起诱导高水平的选择性细胞死亡。最后，在接受抑制性抗逆转录病毒治疗（ART）的个体的外周血单核细胞（PBMC）和CD4（+）T细胞中离体检测到高水平的细胞相关HIV RNA。尽管在 PBMC 中未检测到该组合的协同作用，但 CD4(+) T 细胞中的病毒 RNA 表达显着增加。总的来说，这些结果通过证明先天免疫激活和表观遗传调节在减少病毒库和诱导 HIV 感染细胞特异性死亡方面的潜力，代表着朝着根除 HIV 迈出了有希望的一步。 重要性 与 HIV-1 感染相关的挑战之一是，尽管抗逆转录病毒疗法将 HIV-1 载量降低到不可检测的水平，但前病毒 DNA 在 T 淋巴细胞亚群中仍然处于休眠状态。已经提出了许多通过重新激活潜伏病毒和消除HIV-1储存库来清除残留病毒的策略（所谓的“休克杀死”策略）。在本研究中，我们使用激活 cGAS-STING 抗病毒先天免疫反应（双环核苷酸 cGAMP）的小分子和表观遗传调节剂（组蛋白脱乙酰酶抑制剂）的组合，诱导细胞系、原代 T 淋巴细胞和患者样本中 HIV 感染 T 细胞的重新激活和杀伤。这些研究代表了一种通过减少病毒库和诱导艾滋病毒感染细胞特异性死亡来根除艾滋病毒的新策略。
The presence of T cell reservoirs in which human immunodeficiency virus (HIV) establishes latency by integrating into the host genome represents a major obstacle to an HIV cure and has prompted the development of strategies aimed at the eradication of HIV from latently infected cells. The "shock-and-kill" strategy is one of the most pursued approaches to the elimination of viral reservoirs. Although several latency-reversing agents (LRAs) have shown promising reactivation activity, they have failed to eliminate the cellular reservoir. In this study, we evaluated a novel immune system-mediated approach to clearing the HIV reservoir, based on a combination of innate immune stimulation and epigenetic reprogramming. The combination of the STING agonist cGAMP (cyclic GMP-AMP) and the FDA-approved histone deacetylase inhibitor resminostat resulted in a significant increase in HIV proviral reactivation and specific apoptosis in HIV-infected cells in vitro. Reductions in the proportion of HIV-harboring cells and the total amount of HIV DNA were also observed in CD4(+) central memory T (T-CM) cells, a primary cell model of latency, where resminostat alone or together with cGAMP induced high levels of selective cell death. Finally, high levels of cell-associated HIV RNA were detected ex vivo in peripheral blood mononuclear cells (PBMCs) and CD4(+) T cells from individuals on suppressive antiretroviral therapy (ART). Although synergism was not detected in PBMCs with the combination, viral RNA expression was significantly increased in CD4(+) T cells. Collectively, these results represent a promising step toward HIV eradication by demonstrating the potential of innate immune activation and epigenetic modulation for reducing the viral reservoir and inducing specific death of HIV-infected cells.IMPORTANCE One of the challenges associated with HIV-1 infection is that despite antiretroviral therapies that reduce HIV-1 loads to undetectable levels, proviral DNA remains dormant in a subpopulation of T lymphocytes. Numerous strategies to clear residual virus by reactivating latent virus and eliminating the reservoir of HIV-1 (socalled "shock-and-kill" strategies) have been proposed. In the present study, we use a combination of small molecules that activate the cGAS-STING antiviral innate immune response (the di-cyclic nucleotide cGAMP) and epigenetic modulators (histone deacetylase inhibitors) that induce reactivation and HIV-infected T cell killing in cell lines, primary T lymphocytes, and patient samples. These studies represent a novel strategy for HIV eradication by reducing the viral reservoir and inducing specific death of HIV-infected cells.