DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition.
DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition.
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DOI：
10.1186/1742-4690-10-21
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发表时间：
2013-02-21
期刊：
影响因子：
3.3
通讯作者：
Ishizaka Y
中科院分区：
文献类型：
--
作者：
Koyama T;Sun B;Tokunaga K;Tatsumi M;Ishizaka Y
预防持续性人类免疫缺陷病毒 1 型 (HIV-1) 感染需要澄清病毒转导至静息巨噬细胞的模式。最近，DNA 双链断裂 (DSB) 被证明可以增强 D64A 病毒的感染，该病毒具有缺陷的整合酶催化活性 (IN-CA)。然而，DSB 上调病毒转导的机制尚不清楚。在这里，我们分析了 DSB 在不依赖 IN-CA 的病毒转导至巨噬细胞过程中的作用。我们使用具有稀切核酸内切酶的细胞系统，发现 D64A 病毒有效整合到人工诱导的 DSB 位点中。这种不依赖于 IN-CA 的病毒转导被共济失调毛细血管扩张突变蛋白 (ATM) 抑制剂阻断，但对链转移过程中整合酶活性抑制剂拉替拉韦 (RAL) 具有耐药性。此外，Vpr（HIV-1的辅助基因产物）可诱导静息巨噬细胞中的DSB，并显着提高不依赖于IN-CA的病毒转导至巨噬细胞的速率，同时产生次级病毒。 DSB 有助于巨噬细胞的 IN-CA 独立病毒感染，而巨噬细胞对 RAL 具有抗性。因此，ATM依赖性细胞途径和Vpr诱导的DNA损伤是预防持续性HIV-1感染的新靶点。
The prevention of persistent human immunodeficiency virus type 1 (HIV-1) infection requires the clarification of the mode of viral transduction into resting macrophages. Recently, DNA double-strand breaks (DSBs) were shown to enhance infection by D64A virus, which has a defective integrase catalytic activity (IN-CA). However, the mechanism by which DSBs upregulate viral transduction was unclear. Here we analyzed the roles of DSBs during IN-CA–independent viral transduction into macrophages. We used cellular systems with rare-cutting endonucleases and found that D64A virus integrated efficiently into the sites of artificially induced DSBs. This IN-CA-independent viral transduction was blocked by an inhibitor of ataxia telangiectasia mutated protein (ATM) but was resistant to raltegravir (RAL), an inhibitor of integrase activity during strand transfer. Moreover, Vpr, an accessory gene product of HIV-1, induced DSBs in resting macrophages and significantly enhanced the rate of IN-CA-independent viral transduction into macrophages with concomitant production of secondary viruses. DSBs contribute to the IN-CA–independent viral infection of macrophages, which is resistant to RAL. Thus, the ATM-dependent cellular pathway and Vpr-induced DNA damage are novel targets for preventing persistent HIV-1 infection.
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影响因子：
14.9
作者：
Farkash EA;Kao GD;Horman SR;Prak ET
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