Objectives

Current antiretroviral therapy can suppress HIV replication, increase CD4 count and result in increased lifespan. However, it cannot eradicate the virus due to the presence of latent provirus in cellular reservoirs, such as resting CD4+ T cells. Using combination latency-reversing agents to shock the virus out of latency for elimination through immune clearance or viral cytopathic effect is one of the most promising strategies for HIV eradication. Specifically, recent evidence shows that isoform-selective histone deacetylase inhibitors may be more effective than their non-selective counterparts. Therefore, identification and characterisation of new isoform-selective compounds are of prime importance. Here, we sought to determine the ability of two new isoform-targeted hydroxamic acid derivatives to reactivate HIV from latency.

Methods

We used cell lines and infected primary resting CD4+ T cells. These were treated with these compounds with HIV reactivation measured using fluorescence-activated cell sorting, Western blots and luciferase luminescence. Isoform selectivity and acetylation of the HIV promoter were measured by Western blotting and chromatic immunoprecipitation.

Results and conclusions

The two new hydroxamic acid derivatives, MC2625 and MC1742, potently reactivate HIV from latency. These compounds are isoform-selective histone deacetylate inhibitors that increase the levels of histone acetylation at the HIV promoter. In addition, they synergise effectively with the protein kinase C modulators bryostatin-1 and INDY, an inhibitor of the dual-specificity tyrosine phosphorylation regulated kinase 1A. We conclude that the combinations of new hydroxamic acid derivatives and bryostatin-1 or INDY could be a new tool for HIV reactivation in the cure efforts.

中文翻译：

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鉴定可有效延缓HIV潜伏期的同工型选择性异羟肟酸衍生物

目标

当前的抗逆转录病毒疗法可以抑制HIV复制，增加CD4计数并延长寿命。但是，由于潜伏的前病毒在细胞贮存器（如静止的CD4 + T细胞）中的存在，它无法根除病毒。使用组合潜伏期逆转剂通过免疫清除或病毒细胞病变效应使病毒摆脱潜伏期而消除潜伏期，这是消除HIV的最有希望的策略之一。具体而言，最近的证据表明，同种型选择性组蛋白脱乙酰基酶抑制剂可能比其非选择性对应物更有效。因此，新异构体选择性化合物的鉴定和表征至关重要。在这里，我们试图确定两种新的针对异形的异羟肟酸衍生物从潜伏期重新激活HIV的能力。

方法

我们使用细胞系和感染的原代静息CD4 + T细胞。用这些化合物处理这些化合物，并用荧光激活的细胞分选，Western印迹和荧光素酶发光测定其HIV的活化。HIV启动子的同工型选择性和乙酰化通过Western印迹和彩色免疫沉淀法测定。

结果与结论

两种新的异羟肟酸衍生物MC2625和MC1742可以有效地使HIV重新活化。这些化合物是同种型选择性组蛋白去乙酰化抑制剂，可增加HIV启动子上组蛋白乙酰化的水平。此外，它们与蛋白激酶C调节剂bryostatin-1和INDY（双特异性酪氨酸磷酸化调节激酶1A的抑制剂）有效协同作用。我们得出的结论是，新的异羟肟酸衍生物与bryostatin-1或INDY的组合可能是治疗工作中HIV激活的新工具。