In humans, infection with HIV-1 is associated with loss of CD4⁺ T cells, causing severe immunodeficiency and progression to AIDS. By contrast, some non-human primates (NHPs), which are natural hosts of the closely related SIV, are tolerant of SIV infection despite showing high levels of viraemia. Interestingly, CD4⁺ T cell death in humans mostly effects quiescent cells that are not productively infected (that is, they show no evidence of HIV reverse transcription or integration into the genome). Shan and colleagues now demonstrate that human CD4⁺ T cells die by pyroptosis in response to HIV viral entry. This is induced by activation of the CARD8 inflammasome by the viral protease, which is released from the virion during or shortly after cell entry. In activated T cells, T cell receptor (TCR) signalling seems to inhibit CARD8 activation and render the cells permissive to productive infection. Humanized mice reconstituted with CARD8-deficient T cells showed significantly lower levels of T cell depletion after HIV infection, despite high levels of viraemia. Notably, the authors identified loss-of function CARD8 mutations in NHP species that are tolerant to SIV, which may explain the non-pathogenic nature of the infection in these animals.

在人类中，感染 HIV-1 会导致 CD4 ⁺ T 细胞丧失，从而导致严重的免疫缺陷并发展为艾滋病。相比之下，一些非人类灵长类动物 (NHP) 是密切相关的 SIV 的天然宿主，尽管表现出高水平的病毒血症，但它们仍能耐受 SIV 感染。有趣的是，人类 CD4 ⁺ T 细胞死亡主要影响未有效感染的静止细胞（即，它们没有显示出 HIV 逆转录或整合到基因组中的证据）。Shan 及其同事现在证明，人类 CD4 ⁺ T 细胞在 HIV 病毒进入时会因细胞焦亡而死亡。这是由病毒蛋白酶激活 CARD8 炎性体诱导的，病毒蛋白酶在进入细胞期间或进入细胞后不久从病毒颗粒中释放出来。在激活的 T 细胞中，T 细胞受体 (TCR) 信号传导似乎会抑制 CARD8 激活并使细胞允许生产性感染。尽管病毒血症水平较高，但用 CARD8 缺陷 T 细胞重组的人源化小鼠在 HIV 感染后表现出显着较低的 T 细胞消耗水平。值得注意的是，作者在对 SIV 具有耐受性的 NHP 物种中发现了功能丧失的CARD8突变，这可能解释了这些动物感染的非致病性。