Fimepinostat 是一种新型 HDAC 和 PI3K 双重抑制剂，可在没有 T 细胞激活的情况下有效逆转 HIV-1 体外潜伏期。,Journal of Virus Eradication

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Fimepinostat 是一种新型 HDAC 和 PI3K 双重抑制剂，可在没有 T 细胞激活的情况下有效逆转 HIV-1 体外潜伏期。
Journal of Virus Eradication ( IF 3.5 ) Pub Date : 2019-09-18
Jesper D Gunst _{1,

2} , Kathrine Kjær _{1,

2} , Rikke Olesen _{1,

2} , Thomas A Rasmussen _{1,

2} , Lars Østergaard _{1,

2} , Paul W Denton _{1,

2} , Ole S Søgaard _{1,

2} , Martin Tolstrup _{1,

2}

Affiliation

目的测试非美司他 (CUDC-907) 的潜力，它是组蛋白去乙酰化酶 (HDAC) 和磷脂酰肌醇-3-激酶 (PI3K) 的双重抑制剂，可逆转人类免疫缺陷病毒 1 型 (HIV-1) 在感染细胞系中的潜伏期和在长期联合抗逆转录病毒治疗 (cART) 中来自 HIV-1 感染供体的 CD4+ T 细胞中。方法潜在 HIV-1 感染的 J-lat Tat-GFP 和 ACH-2 细胞系用临床相关浓度的非美匹诺他刺激，使用 HDAC 抑制剂 (HDACi) 帕比司他和罗米地辛进行比较。接下来，在体外刺激长期 cART 上感染 HIV-1 的供体的 CD4+ T 细胞，并测量细胞相关的未剪接 HIV-1 RNA 以量化 HIV-1 转录的变化。最后，使用来自未感染供体的外周血单核细胞确定非美匹诺他对 T 细胞活化（CD69 表达）和增殖（Ki67 表达）的影响。结果我们发现fimepinostat 是一种有效的潜伏期逆转剂。这在两个潜伏感染的细胞系以及从 HIV-1 供体分离的 CD4+ T 细胞离体中都是如此。相对于治疗剂量水平，fimepinostat 显示出与 romidepsin 相当的潜伏期逆转潜力，romidepsin 是 HIV-1 治愈相关试验中测试的最有效的 HDACi。有趣的是，与 romidepsin 相比，fimepinostat 刺激导致 T 细胞活化降低并且对 T 细胞增殖没有负面影响。结论在治疗浓度下，HDAC 和 PI3K 双重抑制剂 fimepinostat 是一种有效的 HIV-1 潜伏期逆转剂，它不会诱导 T 细胞活化和增殖。fimepinostat 作为潜伏期逆转剂的潜力值得进一步研究。

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Fimepinostat, a novel dual inhibitor of HDAC and PI3K, effectively reverses HIV-1 latency ex vivo without T cell activation.

OBJECTIVES To test the potential of fimepinostat (CUDC-907), a dual inhibitor of histone deacetylases (HDAC) and phosphatidylinositol-3-kinases (PI3K), to reverse human immunodeficiency virus type 1 (HIV-1) latency in infected cell lines and in CD4+ T cells from HIV-1-infected donors on long-term combination antiretroviral therapy (cART). METHODS Latently HIV-1-infected J-lat Tat-GFP and ACH-2 cell lines were stimulated with clinically relevant concentrations of fimepinostat using the HDAC inhibitors (HDACi) panobinostat and romidepsin for comparison. Next, CD4+ T cells from donors living with HIV-1 on long-term cART were stimulated ex vivo and cell-associated unspliced HIV-1 RNA was measured to quantify changes in HIV-1 transcription. Finally, the impact of fimepinostat on T cell activation (CD69 expression) and proliferation (Ki67 expression) was determined using peripheral blood mononuclear cells from uninfected donors. RESULTS We found fimepinostat to be a potent latency-reversing agent. This was true in two latently infected cell lines as well as ex vivo in CD4+ T cells isolated from donors living with HIV-1. Relative to therapeutic dosing levels, fimepinostat showed latency-reversing potential comparable to romidepsin, which is the most potent HDACi tested in HIV-1 cure-related trials. Interestingly, in contrast to romidepsin, fimepinostat stimulation resulted in decreased T cell activation and had no negative impact on T cell proliferation. CONCLUSIONS At therapeutic concentration, the dual HDAC and PI3K inhibitor fimepinostat was a potent HIV-1 latency-reversing agent and it did not induce T cell activation and proliferation. The potential of fimepinostat as a latency-reversing agent warrants further investigation.

更新日期：2019-11-01

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