DNA damage induces a SAMHD1-mediated block to the infection of macrophages by HIV-1.
DNA damage induces a SAMHD1-mediated block to the infection of macrophages by HIV-1.
复制标题
DOI：
10.1038/s41598-018-22432-4
复制
发表时间：
2018-03-07
影响因子：
4.6
通讯作者：
Landau NR
中科院分区：
文献类型：
--
作者：
Jáuregui P;Landau NR
单核细胞衍生的巨噬细胞（MDM）是HIV-1的重要靶点，尽管SAMHD 1是HIV-1缺乏对抗辅助蛋白的骨髓限制因子。SAMHD 1的抗病毒活性通过细胞周期蛋白依赖性激酶（CDK）磷酸化T592来调节。我们发现，用新制癌素（一种在基因组DNA中引入双链断裂（DBS）的化合物）治疗MDM，导致磷酸化SAMHD 1减少，激活其抗病毒活性并阻断HIV-1感染。这种效应对DSB是特异性的，因为UV光照射诱导的DNA损伤不影响SAMHD 1磷酸化，也不阻断感染。对感染的阻断是在逆转录时，并被Vpx抵消，表明它是由SAMHD 1引起的。新制癌素治疗还激活了先天免疫应答，诱导干扰素刺激基因，但这与HIV-1感染的阻断无关，因为干扰素阻断抗体不能缓解这种免疫应答。作为对新癌抑制素诱导的DNA损伤的响应，CDK抑制剂p21 cip 1的水平增加，这可以解释磷酸化SAMHD 1的减少。结果表明，MDM对HIV-1感染的易感性可以受到改变SAMHD 1磷酸化状态的刺激的影响，其中之一是DNA损伤反应。
Monocyte-derived macrophages (MDMs) are an important target for HIV-1 despite SAMHD1, a myeloid restriction factor for which HIV-1 lacks a counteracting accessory protein. The antiviral activity of SAMHD1 is modulated by phosphorylation of T592 by cyclin-dependent kinases (CDK). We show that treatment of MDMs with neocarzinostatin, a compound that introduces double strand breaks (DBS) in genomic DNA, results in the decrease of phosphorylated SAMHD1, activating its antiviral activity and blocking HIV-1 infection. The effect was specific for DSB as DNA damage induced by UV light irradiation did not affect SAMHD1 phosphorylation and did not block infection. The block to infection was at reverse transcription and was counteracted by Vpx, demonstrating that it was caused by SAMHD1. Neocarzinostatin treatment also activated an innate immune response that induced interferon-stimulated genes but this was not involved in the block to HIV-1 infection, as it was not relieved by an interferon-blocking antibody. In response to Neocarzinostatin-induced DNA damage, the level of the CDK inhibitor p21cip1 increased which could account for the decrease of phosphorylated SAMHD1. The results show that the susceptibility of MDMs to HIV-1 infection can be affected by stimuli that alter the phosphorylation state of SAMHD1, one of which is the DNA damage response.