HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration
HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration
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DOI：
10.1038/nature12274
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发表时间：
2013-06-20
期刊：
影响因子：
64.8
通讯作者：
Nabel, Gary J.
中科院分区：
文献类型：
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作者：
Cooper, Arik;Garcia, Mayra;Nabel, Gary J.
人类免疫缺陷病毒-1（HIV-1）已感染全球6000多万人，并导致近3000万人死亡（1），最终是CD 4（+）T细胞溶细胞感染的结果。在人类和猕猴模型中，这些细胞中的大多数含有病毒DNA，并在病毒血症高峰时迅速消除（2-4），但HIV-1诱导辅助性T细胞死亡的机制尚未确定。在这里，我们表明，病毒诱导的细胞杀伤是由病毒整合引发的。感染野生型HIV-1，而不是整合酶缺陷型突变体，诱导活化的初级CD 4淋巴细胞死亡。同样，药物整合酶抑制剂雷特格韦（raltegravir）在细胞培养和急性感染受试者的CD 4（+）T细胞中消除了HIV-1诱导的细胞杀伤。病毒整合过程中的杀伤机制涉及DNA依赖性蛋白激酶（DNA-PK）的激活，DNA-PK是DNA损伤反应的中心整合剂，其引起p53和组蛋白H2 AX的磷酸化。药理学抑制DNA-PK废除HIV-1感染过程中的细胞死亡在体外，这表明过程中，减少CD 4细胞中的DNA-PK活化，可以促进潜伏感染的细胞，在体内引起水库的形成。我们认为，在病毒整合过程中DNA-PK的激活在CD 4（+）T细胞耗竭中起着重要作用，这增加了整合酶抑制剂和针对DNA-PK的干预措施可能改善感染个体的T细胞存活和免疫功能的可能性。
Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide(1), ultimately the consequence of cytolytic infection of CD4(+) T cells. In humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia(2-4), yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4(+) T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA-PK abolished cell death during HIV-1 infection in vitro, suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo. We propose that activation of DNA-PK during viral integration has a central role in CD4(+) T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals.