The persistence of latent HIV-1 reservoirs throughout combination antiretroviral therapy (cART) is a major barrier on the path to achieving a cure for AIDS. It has been shown that bromodomain and extra-terminal (BET) inhibitors could reactivate HIV-1 latency, but restrained from clinical application due to their toxicity and side effects. Thus, identifying a new type of BET inhibitor with high degrees of selectivity and safety is urgently needed. Apabetalone is a small-molecule selective BET inhibitor specific for second bromodomains, and has been evaluated in phase III clinical trials that enrolled patients with high-risk cardiovascular disorders, dyslipidemia, and low HDL cholesterol. In the current study, we examined the impact of apabetalone on HIV-1 latency. We showed that apabetalone (10-50 μmol/L) dose-dependently reactivated latent HIV-1 in 4 types of HIV-1 latency cells in vitro and in primary human CD4+ T cells ex vivo. In ACH2 cells, we further demonstrated that apabetalone activated latent HIV-1 through Tat-dependent P-TEFB pathway, i.e., dissociating bromodomain 4 (BDR4) from the HIV-1 promoter and recruiting Tat for stimulating HIV-1 elongation. Furthermore, we showed that apabetalone (10-30 μmol/L) caused dose-dependent cell cycle arrest at the G1/G0 phase in ACH2 cells, and thereby induced the preferential apoptosis of HIV-1 latent cells to promote the death of reactivated reservoir cells. Notably, cardiovascular diseases and low HDL cholesterol are known as the major side effects of cART, which should be prevented by apabetalone. In conclusion, apabetalone should be an ideal bifunctional latency-reversing agent for advancing HIV-1 eradication and reducing the side effects of BET inhibitors.

中文翻译：

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病毒激活后，BET溴结构域抑制剂apabetalone诱导了潜在的HIV-1储藏细胞凋亡。

在联合抗逆转录病毒疗法（cART）中，潜在的HIV-1储库的持久存在是实现艾滋病治愈途径的主要障碍。已经显示溴结构域和末端外（BET）抑制剂可以重新激活HIV-1潜伏期，但由于其毒性和副作用而被限制在临床应用中。因此，迫切需要鉴定具有高度选择性和安全性的新型BET抑制剂。Apabetalone是特异性针对第二个溴结构域的小分子选择性BET抑制剂，已经在III期临床试验中进行了评估，该试验招募了患有高危心血管疾病，血脂异常和低HDL胆固醇的患者。在本研究中，我们检查了阿帕贝龙对HIV-1潜伏期的影响。我们显示，apabetalone（10-50μmol/ L）在体外和体外原代人CD4 + T细胞中的4种类型的HIV-1潜伏期细胞中剂量依赖性地重新激活潜在的HIV-1。在ACH2细胞中，我们进一步证明了apabetalone通过Tat依赖的P-TEFB途径激活了潜在的HIV-1，即从HIV-1启动子上解离了溴结构域4（BDR4），并募集Tat来刺激HIV-1的延伸。此外，我们表明，阿帕贝酮（10-30μmol/ L）在ACH2细胞中引起剂量依赖性细胞周期停滞在ACH2细胞的G1 / G0期，从而诱导HIV-1潜伏细胞的优先凋亡，从而促进重新活化的水库死亡。细胞。值得注意的是，心血管疾病和低HDL胆固醇是cART的主要副作用，应通过阿帕贝单独预防。综上所述，