Selection of epigenetically privileged HIV-1 proviruses during treatment with panobinostat and interferon-α2a.
Selection of epigenetically privileged HIV-1 proviruses during treatment with panobinostat and interferon-α2a.
复制标题
在帕比司他和干扰素-α2a 治疗过程中选择表观遗传学上优先的 HIV-1 前病毒。
DOI：
10.1016/j.cell.2024.01.037
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发表时间：
2024
期刊：
影响因子：
64.5
通讯作者：
Giguel,Franc
中科院分区：
文献类型：
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作者：
Armani-Tourret,Marie;Gao,Ce;Hartana,CiputraAdijaya;Sun,WeiWei;Carrere,Leah;Vela,Liliana;Hochroth,Alexander;Bellefroid,Maxime;Sbrolla,Amy;Shea,Katrina;Flynn,Theresa;Roseto,Isabelle;Rassadkina,Yelizaveta;Lee,Carole;Giguel,Franc
尽管接受了抗逆转录病毒药物的治疗，但潜伏着HIV-1感染的CD4+T细胞仍然存在，这是治愈HIV-1感染的主要障碍。病毒潜伏期的药理破坏可能会使HIV-1感染细胞暴露在宿主免疫活动中，但潜伏期逆转药物在减少HIV-1持久性方面的临床效果仍有待证实。在这里，我们在一项随机对照的人类临床试验中表明，当组蛋白去乙酰化酶抑制剂Panobinostat与聚乙二醇化干扰素-ZNF2a联合使用时，可以诱导α-1存储细胞池的结构变化，其特征是整合在ZNF基因和H3K27ac标记减少的染色质区域的HIV-1前病毒不成比例地过度表达，而H3K27ac标记减少是Panobinostat的分子靶点。相比之下，H3K27ac标记附近的前病毒并未被积极选择，可能是因为对Panobinostat的易感性增加。这些数据表明，潜伏期逆转治疗可以增加HIV-1储存细胞的免疫脆弱性，并加速选择具有表观遗传学特权的HIV-1前病毒。
CD4+T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses.