Division of Infection and Immunity, UCL, London, UK
Macromolecular Structure Laboratory, The Francis Crick Institute, London, UK.
EMBO J. 2018 Jan 4;37(1):50-62. doi: 10.15252/embj.201796880. Epub 2017 Oct 30.
We report that DNA damage induced by topoisomerase inhibitors, including etoposide (ETO), results in a potent block to HIV-1 infection in human monocyte-derived macrophages (MDM). SAMHD1 suppresses viral reverse transcription (RT) through depletion of cellular dNTPs but is naturally switched off by phosphorylation in a subpopulation of MDM found in a G1-like state. We report that SAMHD1 was activated by dephosphorylation following ETO treatment, along with loss of expression of MCM2 and CDK1, and reduction in dNTP levels. Suppression of infection occurred after completion of viral DNA synthesis, at the step of 2LTR circle and provirus formation. The ETO-induced block was completely rescued by depletion of SAMHD1 in MDM Concordantly, infection by HIV-2 and SIVsm encoding the SAMHD1 antagonist Vpx was insensitive to ETO treatment. The mechanism of DNA damage-induced blockade of HIV-1 infection involved activation of p53, p21, decrease in CDK1 expression, and SAMHD1 dephosphorylation. Therefore, topoisomerase inhibitors regulate SAMHD1 and HIV permissivity at a post-RT step, revealing a mechanism by which the HIV-1 reservoir may be limited by chemotherapeutic drugs.
我们报告称，拓扑异构酶抑制剂（包括依托泊苷（ETO））引起的 DNA 损伤会导致人单核细胞衍生的巨噬细胞（MDM）中 HIV-1 感染的强烈阻断。SAMHD1 通过耗尽细胞内的 dNTP 来抑制病毒逆转录（RT），但在处于 G1 样状态的 MDM 亚群中会被磷酸化自然关闭。我们报告称，ETO 处理后 SAMHD1 通过去磷酸化而被激活，同时 MCM2 和 CDK1 的表达丧失，dNTP 水平降低。感染抑制发生在病毒 DNA 合成完成后，在 2LTR 环和前病毒形成的步骤。在 MDM 中耗尽 SAMHD1 可完全挽救 ETO 诱导的阻断。HIV-2 和 SIVsm 编码 SAMHD1 拮抗剂 Vpx 的感染对 ETO 处理不敏感。DNA 损伤诱导的 HIV-1 感染阻断的机制涉及 p53、p21 的激活、CDK1 表达的降低和 SAMHD1 的去磷酸化。因此，拓扑异构酶抑制剂在 RT 后步骤调节 SAMHD1 和 HIV 的易感性，揭示了 HIV-1 储存库可能受化疗药物限制的机制。
