International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
mBio. 2024 Sep 11;15(9):e0163224. doi: 10.1128/mbio.01632-24. Epub 2024 Aug 13.
The HIV reservoir is more dynamic than previously thought with around 70% of the latent reservoir originating from viruses circulating within 1 year of the initiation of antiretroviral therapy (ART). In an model system of HIV latency, it was reported that early exposure to class I histone deacetylase (HDAC) inhibitors might prevent these more recently infected cells from entering a state of stable viral latency. This finding raises the possibility that co-administration of HDAC inhibitors at the time of ART initiation may prevent the establishment of much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and panobinostat co-administered at the time of ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. As previously shown, SAHA and panobinostat were well tolerated in humanized mice. Unexpectedly, co-administration of SAHA resulted in an increase in the frequency of CD4 cells carrying HIV DNA but did not alter the frequency of cell-associated HIV RNA in HIV-infected, ART-treated humanized mice. Co-administration of panobinostat did not alter levels of cell-associated HIV DNA or RNA. Our findings indicate that co-administration of HDAC inhibitors initiated at the same time of ART treatment does not prevent recently infected cells from entering latency.IMPORTANCECurrent antiretroviral therapy (ART) does not eradicate cells harboring replication-competent HIV reservoir. Withdrawal of ART inevitably results in a rapid viremia rebound. The HIV reservoir is more dynamic than previously thought. Early exposure to class I histone deacetylase (HDAC) inhibitors inhibit these more recently infected cells from entering a state of stable viral latency in an model of latency, raising the possibility that co-administration of HDAC inhibitors at the time of ART initiation may reduce much of the HIV reservoir. Here, we tested the effects of the HDAC inhibitors suberoylanilide hydroxamic acid or panobinostat during ART initiation on the formation of the viral reservoir in HIV-infected humanized mice. Our study indicates that in contrast to observations, the co-administration of HDAC inhibitors at the same time of ART initiation does not prevent recently infected cells from entering latency.
HIV 储存库比以前认为的更具动态性，约 70%的潜伏储存库源自抗逆转录病毒治疗 (ART) 开始后 1 年内循环的病毒。在 HIV 潜伏期的模型系统中，据报道，早期接触 I 类组蛋白去乙酰化酶 (HDAC) 抑制剂可能阻止这些最近感染的细胞进入稳定病毒潜伏期的状态。这一发现提出了这样一种可能性，即在开始 ART 时联合使用 HDAC 抑制剂可能阻止大部分 HIV 储存库的建立。在这里，我们测试了在开始 ART 时联合使用 HDAC 抑制剂琥珀酰亚胺羟肟酸 (SAHA) 和帕比司他对感染 HIV 的人源化小鼠中病毒储存库形成的影响。如前所述，SAHA 和帕比司他在人源化小鼠中耐受性良好。出乎意料的是，SAHA 的联合使用导致携带 HIV DNA 的 CD4 细胞的频率增加，但并未改变 HIV 感染、ART 治疗的人源化小鼠中细胞相关 HIV RNA 的频率。帕比司他的联合使用并未改变细胞相关 HIV DNA 或 RNA 的水平。我们的研究结果表明，在开始 ART 治疗的同时联合使用 HDAC 抑制剂并不能阻止最近感染的细胞进入潜伏期。
目前的抗逆转录病毒治疗 (ART) 并不能根除携带具有复制能力的 HIV 储存库的细胞。ART 的停药不可避免地导致病毒血症迅速反弹。HIV 储存库比以前认为的更具动态性。早期接触 I 类组蛋白去乙酰化酶 (HDAC) 抑制剂可阻止这些最近感染的细胞在潜伏期模型中进入稳定病毒潜伏期的状态，这表明在开始 ART 时联合使用 HDAC 抑制剂可能会减少大部分 HIV 储存库。在这里，我们测试了在开始 ART 时使用 HDAC 抑制剂琥珀酰亚胺羟肟酸或帕比司他对感染 HIV 的人源化小鼠中病毒储存库形成的影响。我们的研究表明，与观察结果相反，在开始 ART 的同时联合使用 HDAC 抑制剂并不能阻止最近感染的细胞进入潜伏期。
