Chloroquine inhibits lytic replication of Kaposi's sarcoma-associated herpesvirus by disrupting mTOR and p38-MAPK activation
Chloroquine inhibits lytic replication of Kaposi's sarcoma-associated herpesvirus by disrupting mTOR and p38-MAPK activation
复制标题
氯喹通过破坏 mTOR 和 p38-MAPK 激活来抑制卡波西肉瘤相关疱疹病毒的裂解性复制。
DOI：
10.1016/j.antiviral.2016.08.010
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发表时间：
2016
影响因子：
7.6
通讯作者：
Kuang Ersheng
中科院分区：
文献类型：
--
作者：
Yang Mengtian;Huang Lu;Li Xiaojuan;Kuang Ersheng
裂解感染是卡波西肉瘤相关疱疹病毒(KSHV)持续感染和致病的关键因素，抑制KSHV裂解复制可有效预防KSHV相关疾病的发生。氯喹(CQ)是一种著名的抗疟疾药物和自噬抑制剂，具有广谱的抗病毒作用，并显示出抗癌治疗的潜力。然而，CQ及其衍生物控制致癌性γ疱疹病毒感染的能力仍不清楚。在这里，我们揭示了CQ抑制KSHV裂解基因的表达和病毒粒子的产生，并在临床可接受的剂量下对KSHV裂解感染的B细胞显示出细胞毒作用。CQ抑制KSHV裂解复制过程中mTOR和p38-MAPK通路的激活，但不抑制潜伏感染。此外，CQ通过一种独特的机制阻止EB病毒(EBV)的裂解复制，该机制被用来阻止病毒粒子的产生，但不影响病毒基因的表达。提示CQ是一种有效的抗KSHV裂解感染药物。我们的发现表明，CQ治疗应被考虑用于控制KSHV相关疾病，特别是用于KSHV与疟疾合并感染的主要用途。
Lytic infection is essential for the persistent infection and pathogenesis of Kaposi's sarcoma-associated herpesvirus (KSHV), and inhibiting KSHV lytic replication may effectively prevent the occurrence of KSHV-related diseases. Chloroquine (CQ), a well-known antimalarial drug and autophagy inhibitor, exerts broad-spectrum antiviral effects and shows anti-cancer therapeutic potential. However, the ability of CQ and its derivatives to control infection of oncogenic γ-herpesvirus remains undefined. Here we reveal that CQ suppresses KSHV lytic gene expression and virion production, and shows cytotoxicity toward KSHV lytically infected B cells at clinically acceptable doses. CQ suppresses mTOR and p38-MAPK pathway activation during KSHV lytic replication but not latent infection. Furthermore, CQ blocks Epstein-Barr virus (EBV) lytic replication via a distinct mechanism that is invoked to block virion production but does not affect viral gene expression. These results suggest that CQ is an effective antiviral drug against KSHV lytic infection. Our findings indicate that CQ treatment should be considered for controlling KSHV-related diseases, particularly for primary use in co-infection of KSHV with malaria.