Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate Latent Pathogenic Human Polyomavirus Replication.
Sirolimus and Other Mechanistic Target of Rapamycin Inhibitors Directly Activate Latent Pathogenic Human Polyomavirus Replication.
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DOI：
10.1093/infdis/jiaa071
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发表时间：
2021-10-13
期刊：
影响因子：
--
通讯作者：
Moore PS
中科院分区：
文献类型：
--
作者：
Alvarez Orellana J;Kwun HJ;Artusi S;Chang Y;Moore PS
人多瘤病毒可在移植患者中重新激活，引起肾病、进行性多灶性白质脑病、默克尔细胞癌、皮炎、皮疹或棘状神经发育不良。西罗莫司和雷帕霉素（mTOR）抑制剂的相关机制靶标是移植免疫抑制剂。目前尚不清楚它们是否直接从潜伏期重新激活多瘤病毒复制，超出其对免疫抑制的一般作用。通过免疫印迹、邻位连接、复制子DNA复制和全病毒免疫荧光试验，测定了BK病毒、JC病毒（JCV）、默克尔细胞多瘤病毒（MCV）、人多瘤病毒7（HPyV7）和棘突发育不良多瘤病毒（TSV）的大T（LT）蛋白在药物处理后的体外表达和周转。mTOR抑制增加了测试的所有5种致病性多瘤病毒的LT蛋白表达。这与LT稳定、靶向这些LT蛋白降解的S期激酶相关蛋白2（Skp2）E3连接酶的减少以及JCV、MCV、TSV和HPyV7的病毒复制增加相关。西罗莫司治疗，而不是钙调磷酸酶抑制剂他克莫司，在患者中常规达到的水平，导致BKV，MCV和HPyV7病毒DNA复制的剂量依赖性增加。在治疗水平，mTOR抑制剂通过Skp2依赖性机制直接激活多瘤病毒复制，揭示了多瘤病毒常见的蛋白抑制潜伏机制。修改现有的多瘤病毒相关疾病移植患者的药物治疗方案可能会减少症状性多瘤病毒复制，同时维持同种异体移植物保留免疫抑制。多瘤病毒具有知之甚少的潜伏生命周期，允许持续终身感染。这项研究表明，多瘤病毒的潜伏期是由多瘤病毒复制蛋白，大T细胞的细胞降解。用于移植免疫抑制的mTOR抑制剂可以抑制这一过程，促进多瘤病毒复制。
Human polyomaviruses can reactivate in transplant patients, causing nephropathy, progressive multifocal leukoencephalopathy, Merkel cell carcinoma, pruritic, rash or trichodysplasia spinulosa. Sirolimus and related mechanistic target of rapamycin (mTOR) inhibitors are transplant immunosuppressants. It is unknown if they directly reactivate polyomavirus replication from latency beyond their general effects on immunosuppression. In vitro expression and turnover of large T (LT) proteins from BK virus, JC virus (JCV), Merkel cell polyomavirus (MCV), human polyomavirus 7 (HPyV7), and trichodysplasia spinulosa polyomavirus (TSV) after drug treatment were determined by immunoblotting, proximity ligation, replicon DNA replication, and whole virus immunofluorescence assays. mTOR inhibition increased LT protein expression for all 5 pathogenic polyomaviruses tested. This correlated with LT stabilization, decrease in the S-phase kinase-associated protein 2 (Skp2) E3 ligase targeting these LT proteins for degradation, and increase in virus replication for JCV, MCV, TSV, and HPyV7. Treatment with sirolimus, but not the calcineurin inhibitor tacrolimus, at levels routinely achieved in patients, resulted in a dose-dependent increase in viral DNA replication for BKV, MCV, and HPyV7. mTOR inhibitors, at therapeutic levels, directly activate polyomavirus replication through a Skp2-dependent mechanism, revealing a proteostatic latency mechanism common to polyomaviruses. Modifying existing drug regimens for transplant patients with polyomavirus-associated diseases may reduce symptomatic polyomavirus replication while maintaining allograft-sparing immunosuppression. Polyomaviruses possess a poorly understood latent life cycle allowing persistent lifelong infection. This study reveals that polyomavirus latency is regulated by cellular degradation of the polyomavirus replication protein, large T. The mTOR inhibitors used in transplant immunosuppression can inhibit this process, promoting polyomavirus replication.
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影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A
DOI：
10.1038/nrmicro2992
发表时间：
2013-04
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
21.3
作者：
Carrano, AC;Eytan, E;Pagano, M
通讯作者：
Pagano, M
影响因子：
8.8
作者：
Lassot, Irena;Mora, Stephan;Desagher, Solange
通讯作者：
Desagher, Solange
影响因子：
2.8
作者：
Oellerich, M;Armstrong, VW;Shaw, LM
通讯作者：
Shaw, LM