Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
J Virol. 2020 Apr 16;94(9). doi: 10.1128/JVI.01845-19.
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 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 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.
临床试验研究组使用组蛋白去乙酰化酶抑制剂（HDACi）逆转 HIV-1 潜伏期，旨在使抗逆转录病毒（ARV）治疗个体中的病毒库暴露于免疫效应物清除，但尚未能降低感染细胞的频率。因此，我们研究了 I 类选择性 HDACi 那他珠单抗和罗米地辛对各种潜伏期逆转和消除的影响，包括病毒剪接、抗原呈递和 CD8 T 细胞功能。在 ARV 抑制个体的 CD4 T 细胞中，两种 HDACi 均显著诱导病毒转录，但不诱导剪接或上清液 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 潜伏期模型中，两种 HDACi 处理的 CD4 T 细胞条件均未诱导克隆脱颗粒。两种 HDACi 还损害了原发性 CD8 T 细胞在病毒抑制测定中的功能，其中那他珠单抗的损害较小。这些发现表明，剪接或无细胞 HIV-1 RNA 比未剪接的 HIV-RNA 更能提示抗原表达，并且可能有助于解释 HDACi 产生 CD8 T 细胞靶标能力有限的原因。
抗逆转录病毒（ARV）药物抑制 HIV-1 复制，但不能治愈感染。这使得 HIV-1 感染者终生需要昂贵的日常药物治疗。此外，已经清楚的是，ARV 治疗并不能完全恢复健康，使个体面临心血管疾病、某些类型的癌症和神经认知障碍的风险增加，并且使他们面临耻辱。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称为组蛋白去乙酰化酶抑制剂（HDACi）的药物，它们有可能使 HIV-1 的隐藏库暴露于免疫系统的清除。不幸的是，迄今为止，HDACi 的临床试验结果令人失望。在当前的研究中，我们整合了许多实验方法，建立了一个模型，该模型提供了对 HDACi 在临床试验中活性有限的深入了解，并为未来的方法提供了方向。
