柳叶刀：戒酒药不仅戒酒，还能“唤醒”艾滋病毒

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近期，墨尔本大学Sharon Lewin教授及其研究团队发现，除了戒酒功效之外，双硫仑药物能够激活潜伏的HIV病毒，有望用于治疗艾滋病，实现“先激活后杀死”策略。相关研究成果于11月16日在线发表在《Lancet HIV》期刊。墨尔本大学Sharon Lewin教授及其研究团队近期发现一种常用戒酒药物，双硫仑（disulfiram），能够激活艾滋病患者体内潜伏的休眠病毒，有望推进治愈艾滋终极目标的实现。

戒酒药双硫仑的新使命：对抗HIV

戒酒硫（安塔布司，Antabuse），也称双硫仑，是一种戒酒药物。服用后，即使接触少量酒也会出现呕吐、面部潮红、头疼、出汗、视力模糊等不适症状，以达到戒酒目的。

双硫仑戒酒机制：通过抑制乙醛脱氢酶活性实现，从而阻止由乙醇转变而来的乙醛向下游乙酸的反应过程，使得体内乙醛含量累积超标，破坏体内大分子物质，最终引发身体不适。

近期，墨尔本大学Sharon Lewin教授及其研究团队发现，除了戒酒功效之外，双硫仑药物能够激活潜伏的HIV病毒，有望用于治疗艾滋病。相关研究成果于11月16日在线发表在《Lancet HIV》期刊。

临床试验：“唤醒”HIV，有望实现“先激活后杀死”策略

目前针对艾滋病多采用抗逆转录病毒治疗（ART），通过复合剂增强抑制HIV病毒复制的疗效。但是这种治疗手段却不能根治艾滋，因为顽劣的HIV病毒会以无活性的病毒库形式潜伏于患者体内。一旦患者停止用药后，潜伏的病毒会伺机而动、卷土重来。这也是“密西西比婴儿”再次被检测出HIV的根本原因。

所以，不少科学家提出“先激活后绝杀”的策略，通过药物唤醒休眠的病毒，再利用药物杀死病毒。目前研究较多的候选药物是组蛋白乙酰酶抑制剂，但是因为其副作用明显，一直未被用于临床。

墨尔本大学Sharon Lewin研究团队对30个艾滋病患者进行了为期3天的双硫仑药物试验，发现服药期间所有患者体内艾滋病毒基因表达量增加。研究人员认为这是一个好的迹象，表明体内潜藏病毒被激活。相比于组蛋白乙酰酶抑制剂，研究人员表示，双硫仑够长时间服用且无副作用，但服药期间需要避免饮酒。

但是，巴斯德研究所Asier Sáez-Cirión表示，仅仅有双硫仑还不够。只有与消灭激活的HIV药物结合使用，才能体内HIV病毒清除或者控制在自身防御系统得以对付的水平，从而避免抗逆转录病毒药物的长期服用。研究团队目前正在寻找与双硫仑结合使用的药物，用于消灭复苏的病毒库。

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参考文献：

Short-term administration of disulfiram for reversal of latent HIV infection

文献检索：DOI: http://dx.doi.org/10.1016/S2352-3018(15)00226-X

Background In vitro, disulfiram activated HIV transcription in a primary T-cell model of HIV latency and in a pilot clinical study increased plasma HIV RNA in individuals with adequate drug exposure. We assessed the effect of disulfiram on HIV transcription in a dose-escalation study. Methods In this prospective dose-escalation study, to optimise disulfiram exposure we included adults with HIV on suppressive antiretroviral therapy, with plasma HIV RNA of less than 50 copies per mL and a CD4 cell count greater than 350 cells per μL. Participants were allocated sequentially to one of three dosing groups (500 mg, 1000 mg, and 2000 mg) and received disulfiram daily for 3 days. Only the staff who did laboratory assays were masked to group assignment. The primary endpoint was change in cell-associated unspliced HIV RNA in CD4 cells. The primary analysis method was a negative binomial regression, with the number of copies as the outcome variable and the input total RNA or plasma volume as an exposure variable, which is equivalent to modelling copies or input. We used these models to estimate changes from before disulfiram to timepoints during and after disulfiram administration. This study is registered with ClinicalTrials.gov, number NCT01944371. Findings Of 34 participants screened for eligibility at The Alfred Hospital (Melbourne, VIC, Australia), and San Francisco General Hospital (San Francisco, CA, USA), 30 people were enrolled between Sept 24, 2013, and March 31, 2014. The estimated fold increases in cell-associated unspliced HIV RNA from baseline were 1·7 (95% CI 1·3–2·2; p<0·0001) to the timepoint during disulfiram treatment and 2·1 (1·5–2·9; p<0·0001) to the timepoint after disulfiram in the 500 mg group; 1·9 (1·6–2·4; p<0·0001) and 2·5 (1·9–3·3; p<0·0001) in the 1000 mg group; and 1·6 (1·2–2·1; p=0·0026) and 2·1 (1·5–3·1; p=0·0001) in the 2000 mg group. No deaths occurred, and no serious adverse events were noted. Disulfiram was well tolerated at all doses. Interpretation Short-term administration of disulfiram resulted in increases in cell-associated unspliced HIV RNA at all doses, consistent with activating HIV latency. Disulfiram may be suited for future studies of combination and prolonged therapy to activate latent HIV. Funding The Foundation for AIDS Research (amfAR); National Institute of Allergy and Infectious Diseases, National Institutes of Health; Australian National Health and Medical Research Council.

来源：生物探索

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