HIV-1 Vpr induces TLR4/MyD88-mediated IL-6 production and reactivates viral production from latency
HIV-1 Vpr induces TLR4/MyD88-mediated IL-6 production and reactivates viral production from latency
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DOI：
10.1189/jlb.0809547
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发表时间：
2010-06-01
影响因子：
5.5
通讯作者：
Ishizaka, Yukihito
中科院分区：
文献类型：
--
作者：
Hoshino, Shigeki;Konishi, Mitsuru;Ishizaka, Yukihito
Vpr是一种HIV-1辅助蛋白，被认为存在于HIV-1阳性患者的血浆中，我们以前的工作证明了52例患者中有20例存在血浆Vpr。有趣的是，我们的数据显示，患者的病毒滴度与血浆中检测到的Vpr水平相关。在这里，我们首先表明，rVpr，当与人单核细胞或MDM孵育，引起潜伏感染的细胞的病毒生产，和IL-6被确定为一个负责任的因素。rVpr对IL-6的诱导依赖于通过TLR 4及其衔接分子MyD 88的信号传导。我们接下来提供的证据表明，rVpr诱导OxPC的形成，并针对OxPC的单克隆抗体阻断rVpr诱导的IL-6的产生，伴随着MAPK激活的减弱。此外，加入NAC，ROS的清除剂，废除rVpr诱导的OxPC的形成，C/EBP-β的磷酸化，MAPK的底物，和IL-6的产生。由于rIL-6在潜伏感染的细胞中重新激活病毒复制，我们的数据表明，rVpr诱导的氧化应激触发基于细胞的先天免疫应答，并通过IL-6的产生重新激活潜伏感染细胞中的病毒产生。我们的研究结果表明，Vpr应根据病毒滴度进行监测，并为开发针对Vpr的新型抗艾滋病治疗药物提供了理论基础。J. Leukoc. 87：1133-1143; 2010.
Vpr, a HIV-1 accessory protein, was believed to be present in the plasma of HIV-1-positive patients, and our previous work demonstrated the presence of plasma Vpr in 20 out of 52 patients. Interestingly, our data revealed that patients' viral titer was correlated with the level of Vpr detected in their plasma. Here, we first show that rVpr, when incubated with human monocytes or MDMs, caused viral production from latently infected cells, and IL-6 was identified as a responsible factor. The induction of IL-6 by rVpr was dependent on signaling through TLR4 and its adaptor molecule, MyD88. We next provide evidence that rVpr induced the formation of OxPC and that a mAb against OxPC blocked rVpr-induced IL-6 production with the concomitant attenuation of MAPK activation. Moreover, the addition of NAC, a scavenger of ROS, abrogated the rVpr-induced formation of OxPC, the phosphorylation of C/EBP-beta, a substrate of MAPK, and IL-6 production. As rIL-6 reactivated viral replication in latently infected cells, our data indicate that rVpr-induced oxidative stress triggers cell-based innate immune responses and reactivates viral production in latently infected cells via IL-6 production. Our results suggest that Vpr should be monitored based on the viral titer, and they provide the rationale for the development of novel, anti-AIDS therapeutics targeting Vpr. J. Leukoc. Biol. 87: 1133-1143; 2010.