Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes.
Inhibition of LSD1 reduces herpesvirus infection, shedding, and recurrence by promoting epigenetic suppression of viral genomes.
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DOI：
10.1126/scitranslmed.3010643
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发表时间：
2014-12-03
影响因子：
17.1
通讯作者：
Kristie TM
中科院分区：
文献类型：
--
作者：
Hill JM;Quenelle DC;Cardin RD;Vogel JL;Clement C;Bravo FJ;Foster TP;Bosch-Marce M;Raja P;Lee JS;Bernstein DI;Krause PR;Knipe DM;Kristie TM
尽管有针对病毒DNA复制的抗病毒药物可用，但疱疹病毒在人群中的高流行率和维持终生潜伏的蓄水池是控制疱疹疾病的挑战。除了口腔和生殖器损害外，单纯疱疹病毒感染和潜伏池的反复激活可导致严重的病理，包括新生儿感染和死亡、眼角膜炎导致的失明，以及免疫抑制个体的病毒引起的并发症。疱疹病毒和它们的细胞宿主一样，受到促进或抑制基因表达的染色质和染色质调制机制的调节影响。单纯疱疹病毒感染的启动和潜伏期的重新激活依赖于转录辅助激活物复合体，该复合体包含两个必需的组蛋白去甲基酶LSD1和JMJD2s。抑制这两种酶中的任何一种都会导致病毒基因组的异色抑制，并阻止感染和体外再激活。在此，在单纯疱疹病毒感染和疾病的三个动物模型中证明了表观遗传抑制病毒感染的概念。通过用单胺氧化酶抑制剂三羟环丙胺处理动物来抑制LSD1，可以抑制病毒的裂解感染、亚临床脱落和体内潜伏期的重新激活。表型抑制与病毒基因组的表观遗传抑制增强相关，并表明即使在潜伏期，病毒的染色质状态也是动态的。鉴于表观药物的不断发展，这种方法在抗疱疹治疗方面具有巨大的潜力，与目前的药物选择相比具有明显的优势。
The high prevalence of Herpesviruses in the population and the maintenance of lifelong latent reservoirs are challenges to the control of herpetic diseases, despite the availability of antiviral pharmaceuticals that target viral DNA replication. In addition to oral and genital lesions, herpes simplex virus infections and recurrent reactivations from the latent pool can result in severe pathology including neonatal infection and mortality, blindness due to ocular keratitis, and viral-induced complications in immunosuppressed individuals. Herpesviruses, like their cellular hosts, are subject to the regulatory impacts of chromatin and chromatin modulation machinery that promotes or suppresses gene expression. The initiation of herpes simplex virus infection and reactivation from latency is dependent on a transcriptional coactivator complex that contains two required histone demethylases, LSD1 and JMJD2s. Inhibition of either of these enzymes results in heterochromatic suppression of the viral genome and a block to infection and reactivation in vitro. Here, the concept of epigenetic suppression of viral infection is demonstrated in three animal models of herpes simplex virus infection and disease. Inhibition of LSD1 via treatment of animals with the monoamine oxidase inhibitor tranylcypromine results in suppression of viral lytic infection, subclinical shedding, and reactivation from latency in vivo. Phenotypic suppression is correlated with enhanced epigenetic suppression of the viral genome and suggests that, even during latency, the chromatin state of the virus is dynamic. Given the expanding development of epipharmaceuticals, this approach has substantial potential for anti-herpetic treatments with distinct advantages over the present pharmaceutical options.
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影响因子：
1.4
作者：
Duffus, WA;Mermin, J;Downing, R
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.1406663111
发表时间：
2014-09-16
影响因子：
11.1
作者：
Hill, Alison L.;Rosenbloom, Daniel I. S.;Siliciano, Robert F.
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