PDF(Pubmed)
Abstract：
While CD4+ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of \"natural\" hosts such as sooty mangabeys does not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4+ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from \"natural hosts,\" which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4+ T cell depletion during pathogenic HIV/SIV infections.
摘要：
虽然CD4+T细胞耗竭是HIV和SIV感染猕猴患者疾病进展的关键，这种消耗背后的机制仍未完全理解，大多数细胞死亡涉及未感染细胞。相比之下,尽管存在高水平病毒血症，但“自然”宿主的SIV感染，例如黑烟芒果并不会引起CD4耗竭和AIDS。这里,我们报告说，CARD8炎性体在HIV进入后立即被包裹在进入的病毒体中的病毒蛋白酶激活。通过CARD8对HIV蛋白酶活性的感知导致静止细胞的快速焦亡而没有生产性感染，而T细胞激活会消除CARD8功能并增加对感染的放纵。在用CARD8缺陷细胞重建的人源化小鼠中，尽管病毒血症较高，但CD4+耗竭延迟。最后,我们在来自天然宿主的CARD8中发现了功能缺失突变，“这可以解释这些感染的特殊非致病性。我们的研究表明，CARD8在致病性HIV/SIV感染期间驱动CD4+T细胞耗竭。
