Mechanisms of inflammasome activation and pyroptosis induction by HIV

未经治疗的患者在HIV进展过程中CD4T细胞的进行性丢失导致了临床综合征艾滋病。在HIV感染过程中，活化的CD4T细胞通过caspase-3介导的细胞凋亡而死亡。然而，在HIV感染期间死亡的绝大多数CD4T细胞(超过95%)是静止的淋巴CD4T细胞。最近发现，这些静止的淋巴样CD4T细胞在HIV感染后经历了caspase-1介导的嗜热性细胞死亡，而不是凋亡。人们认为，在所谓的流产感染过程中会产生异常核酸，并由核酸传感器IFI16直接识别。反过来，IFI16与适配蛋白ASC一起在核旁区域形成一个活跃的炎症体，导致caspase-1的自动蛋白水解性激活。活化的caspase-1蛋白水解性激活IL-1b细胞因子家族的成员，并介导下垂。值得注意的是，外周静止的CD4T细胞不会在HIV感染时死于IFI16介导的下垂，除非它们收到来自淋巴静止的CD4T细胞的信号。细胞类型和激活依赖诱导IFI16炎症体和随后的嗜热性细胞死亡的机制仍不清楚。我们在巨噬细胞中进行了广泛的化学生物学筛选，以更好地了解其他触发因素激活炎症体的机制。我们的初步数据显示，许多特定的信号通路作用于控制炎症体的激活，并影响炎症体对各种触发因素的反应阈值。在这项建议中，我们的目标是扩大这些研究，并在感染艾滋病毒的人淋巴聚集培养(HLAC)中进行化学生物学筛选，以更好地了解推动IFI16炎症小体形成和诱导下垂的机制。通过一个综合的合作研究计划，我们的目标是识别和验证在静止的CD4淋巴CD4T细胞中限制HIV的新因素。我们还旨在验证这些新发现的通路是否更普遍地调节其他类型细胞中其他炎性小体和下垂的形成。

The progressive loss of CD4 T cells during HIV progression in non-treated patients leads to the clinical syndrome AIDS. Activated CD4 T cells die through caspase-3 mediated apoptosis during HIV infection. However, the large majority of CD4 T cells (more than 95%) that die during HIV infection are quiescent lymphoid CD4 T cells. Recently, it has been discovered that these quiescent lymphoid CD4 T cells undergo caspase-1 mediated pyroptotic cell death rather than apoptosis after HIV infection. It is thought that aberrant nucleic acids are produced during the process of so-called abortive infection which are directly recognized by the nuclear nucleic acid sensor IFI16. IFI16, in turn, forms an active inflammasome together with the adapter protein ASC in a paranuclear area leading to auto-proteolytic activation of caspase-1. Active caspase-1 proteolytically activates members of the IL-1b cytokine family and mediates pyroptosis. Of note, peripheral quiescent CD4 T cells do not die from IFI16-mediated pyroptosis upon HIV infection, unless they receive signals from lymphoid quiescent CD4 T cells. The mechanisms underlying the cell type and activation dependent induction of the IFI16 inflammasome and subsequent pyroptotic cell death remain ill defined. We have performed extensive chemical biology screens in macrophages to better understand the mechanisms of inflammasome activation by other triggers. Our preliminary data show that many specific signaling pathways act to control inflammasome activation and influence the threshold of inflammasome responses to various triggers. In this proposal we aim to extend these studies and perform chemical biology screens in human lymphoid aggregate cultures (HLAC) infected with HIV to gain a better understanding of the mechanisms driving IFI16 inflammasome formation and pyroptosis induction. Through an integrated collaborative research plan we aim to identify and verify novel factors acting in HIV restriction in quiescent CD4 lymphoid CD4 T cells. We also aim to verify whether these newly uncovered pathways more generally regulate the formation of other inflammasomes and pyroptosis in other cell types.