1] Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA [2].
Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, California 94158, USA.
Nature. 2014 Jan 23;505(7484):509-14. doi: 10.1038/nature12940.
The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. This death pathway thus links the two signature events in HIV infection-CD4 T-cell depletion and chronic inflammation-and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of 'anti-AIDS' therapeutics targeting the host rather than the virus.
虽然凋亡已被提议作为关键机制，但导致 HIV 感染宿主中 CD4 T 细胞死亡的途径仍知之甚少。我们现在表明，caspase-3 介导的凋亡仅占 CD4 T 细胞死亡的一小部分，这些细胞既被激活又被有效感染。其余超过 95%的静止淋巴细胞 CD4 T 细胞通过 caspase-1 介导的细胞焦亡而死亡，这是由失败的病毒感染引发的。细胞焦亡对应于一种强烈的炎症形式的程序性细胞死亡，其中细胞质内容物和促炎细胞因子，包括 IL-1β，被释放。因此，这种死亡途径将 HIV 感染的两个标志性事件——CD4 T 细胞耗竭和慢性炎症——联系起来，并在其中创建一个致病的恶性循环，其中垂死的 CD4 T 细胞释放炎症信号，吸引更多细胞死亡。通过已被证明在人类中安全的 caspase 1 抑制剂可以打破这种循环，从而为靶向宿主而不是病毒的新型“抗艾滋病”治疗药物提供了可能性。
