Clinical trials investigating histone deacetylase inhibitors (HDACi) to reverse HIV-1 latency aim to expose reservoirs in antiretroviral (ARV)-treated individuals to clearance by immune effectors, yet have not driven measurable reductions in the frequencies of infected cells. We therefore investigated the effects of the class I-selective HDACi nanatinostat and romidepsin on various blocks to latency reversal and elimination, including viral splicing, antigen presentation, and CD8+ T cell function. In ex vivo CD4+ T cells from ARV-suppressed individuals, both HDACi significantly induced viral transcription, but not splicing nor supernatant HIV-1 RNA. In an HIV-1 latency model using autologous CD8+ T cell clones as biosensors of antigen presentation, neither HDACi-treated CD4+ T cell condition induced clone degranulation. Both HDACi also impaired the function of primary CD8+ T cells in viral inhibition assays, with nanatinostat causing less impairment. These findings suggest that spliced or cell-free HIV-1 RNAs are more indicative of antigen expression than unspliced HIV-RNAs and may help to explain the limited abilities of HDACi to generate CD8+ T cell targets in vivo IMPORTANCE Antiretroviral (ARV) drug regimens suppress HIV-1 replication but are unable to cure infection. This leaves people living with HIV-1 burdened by a lifelong commitment to expensive daily medication. Furthermore, it has become clear that ARV therapy does not fully restore health, leaving individuals at elevated risk for cardiovascular disease, certain types of cancers, and neurocognitive disorders, as well as leaving them exposed to stigma. Efforts are therefore under way to develop therapies capable of curing infection. A key focus of these efforts has been on a class of drugs called histone deacetylase inhibitors (HDACi), which have the potential of exposing hidden reservoirs of HIV-1 to elimination by the immune system. Unfortunately, clinical trial results with HDACi have thus far been disappointing. In the current study, we integrate a number of experimental approaches to build a model that provides insights into the limited activity of HDACi in clinical trials and offers direction for future approaches.

中文翻译：

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病毒转录、抗原呈递和 CD8+ T 细胞功能的综合评估揭示了 I 类选择性组蛋白脱乙酰酶抑制剂在 HIV-1 潜伏期逆转过程中的多重局限性。


研究组蛋白脱乙酰酶抑制剂 (HDACi) 逆转 HIV-1 潜伏期的临床试验旨在使接受抗逆转录病毒 (ARV) 治疗的个体的储存库暴露于免疫效应物的清除，但尚未导致受感染细胞频率的显着降低。因此，我们研究了 I 类选择性 HDACi Nanatinostat 和罗米地辛对潜伏期逆转和消除的各种阻断的影响，包括病毒剪接、抗原呈递和 CD8+ T 细胞功能。在来自 ARV 抑制个体的离体 CD4+ T 细胞中，两种 HDACi 均显着诱导病毒转录，但不剪接或上清液 HIV-1 RNA。在使用自体 CD8+ T 细胞克隆作为抗原呈递生物传感器的 HIV-1 潜伏模型中，HDACi 处理的 CD4+ T 细胞条件均未诱导克隆脱粒。在病毒抑制试验中，这两种 HDACi 也会损害原代 CD8+ T 细胞的功能，而nanatinostat 造成的损害较小。这些发现表明，剪接或无细胞的 HIV-1 RNA 比未剪接的 HIV-RNA 更能指示抗原表达，并可能有助于解释 HDACi 在体内生成 CD8+ T 细胞靶标的能力有限。 HIV-1复制但无法治愈感染。这使得 HIV-1 感染者终生承担昂贵的日常药物治疗的负担。此外，很明显，抗逆转录病毒疗法并不能完全恢复健康，使个体患心血管疾病、某些类型的癌症和神经认知障碍的风险升高，并使他们面临耻辱。因此，正在努力开发能够治愈感染的疗法。 这些努力的一个重点是一类名为组蛋白脱乙酰酶抑制剂 (HDACi) 的药物，它有可能暴露隐藏的 HIV-1 病毒库，从而被免疫系统消除。不幸的是，HDACi 的临床试验结果迄今为止令人失望。在当前的研究中，我们整合了多种实验方法来构建一个模型，该模型可以深入了解 HDACi 在临床试验中的有限活性，并为未来的方法提供方向。