Nature2014-06-26 4:52 PM

艾滋病治疗的一个另类方法 Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection


CD4 T细胞(携带能够识别被病毒感染的细胞表面上的CD4抗原的受体的辅助T细胞)的丧失是艾滋病发病的根源。在这项研究中,Warner Greene等人识别出静止的淋巴CD4 T细胞在HIV感染过程中被耗尽的机制。利用保持了天然淋巴环境的人淋巴组织的体外培养,本文作者发现,失败的病毒复制触发由“半胱天冬酶-1”介导的细胞焦亡,后者造成细胞死亡。“半胱天冬酶-1”抑制药物(它们在临床试验中已被发现是安全的)在体外能挽救细胞死亡,这说明可能存在新的一类以主体、而不是以病毒为作用目标的抗艾滋病治疗药物。


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.






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