Manipulation of ILC function and survival by human and simian immunodeficiency viruses

人类和猿猴免疫缺陷病毒对 ILC 功能和存活的操纵

• 批准号: 320361745
• 负责人: Professor Dr. Frank Kirchhoff
• 金额: --
• 依托单位: Institut für Molekulare Virologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/320361745?language=en
• 关键词: Manipulation; ILC; function; survival; human

Chronic inflammation caused by microbial translocation from the gastrointestinal tract into the systemic circulation drives AIDS progression in HIV-1 infected individuals. In striking contrast, chronic immune activation is absent in nonpathogenic SIV infections of natural host species. The mechanisms underlying the destruction of intact intestinal mucosal barrier function and the different clinical outcomes of HIV-1 and well-adapted SIV infections are still poorly understood. Recent data suggest, however, that effects of HIV-1 infection on innate lymphoid cells (ILCs) play an important role in the pathogenesis of AIDS. Most notably, group 3 ILCs (ILC3s) that are essential for maintenance of intestinal barrier function and homeostasis are rapidly depleted in acute HIV-1 infection. Thus, loss of ILC3s most likely plays a key role in the permanent damage of the intestinal mucosal barrier. In the present proposal, we thus want to determine how HIV-1 and other primate lentiviruses affect ILC3 function and survival. It has been suggested that the production of type I interferons (IFNs) by plasmacytoid dendritic cells or MHC-II/TCR-CD3-mediated interactions of ILCs with conventional CD4+ T cells regulate the fate and activity of intestinal ILCs. We have shown that HIV-1 induces higher levels of type I IFN than HIV-2 or simian immunodeficiency viruses (SIVs) and that only the latter are capable of downmodulating the CD3 T cell receptor from the cell surface. Through comparative analyses of HIV-1 with less pathogenic HIV-2 and "non-pathogenic" SIV clones or specific mutants thereof, we will determine the mechanisms responsible for the depletion of ILC3s. Furthermore, we will analyze whether some primate lentiviruses might directly infect and manipulate some types of ILCs. Finally, we will determine whether the accessory viral Vpr, Vpu or Nef proteins might modulate cell surface receptors (such as TCR-CD3) or cytokine expression (e.g. IFNs) by virally infected CD4+ T cell, macrophages or plasmacytoid dendritic cells to modulate ILC function. The results will provide new information on the mechanisms underlying the depletion of ILC populations that are critical for effective innate immunity and the maintenance of intact intestinal barrier function. This knowledge might help to develop new strategies to prevent damaging chronic immune activation in HIV-infected individuals.

由微生物从胃肠道移位到体循环引起的慢性炎症会导致 HIV-1 感染者的艾滋病进展。与此形成鲜明对比的是，自然宿主物种的非致病性 SIV 感染中不存在慢性免疫激活。完整肠粘膜屏障功能被破坏的机制以及 HIV-1 和适应性较强的 SIV 感染的不同临床结果仍然知之甚少。然而，最近的数据表明，HIV-1 感染对先天淋巴细胞 (ILC) 的影响在艾滋病的发病机制中发挥着重要作用。最值得注意的是，对于维持肠道屏障功能和体内平衡至关重要的第 3 组 ILC (ILC3) 在急性 HIV-1 感染中迅速耗尽。因此，ILC3 的缺失很可能在肠粘膜屏障的永久性损伤中发挥关键作用。因此，在本提案中，我们希望确定 HIV-1 和其他灵长类慢病毒如何影响 ILC3 功能和存活。有人提出，浆细胞样树突状细胞产生 I 型干扰素 (IFN) 或 MHC-II/TCR-CD3 介导的 ILC 与常规 CD4+ T 细胞的相互作用调节肠道 ILC 的命运和活性。我们已经证明，HIV-1 比 HIV-2 或猿猴免疫缺陷病毒 (SIV) 诱导更高水平的 I 型干扰素，并且只有后者能够下调细胞表面的 CD3 T 细胞受体。通过对HIV-1与致病性较低的HIV-2和“非致病性”SIV克隆或其特定突变体进行比较分析，我们将确定导致ILC3耗竭的机制。此外，我们将分析一些灵长类慢病毒是否可能直接感染和操纵某些类型的ILC。最后，我们将确定辅助病毒 Vpr、Vpu 或 Nef 蛋白是否可能通过病毒感染的 CD4+ T 细胞、巨噬细胞或浆细胞样树突状细胞调节细胞表面受体（例如 TCR-CD3）或细胞因子表达（例如 IFN），从而调节 ILC 功能。这些结果将提供有关 ILC 群体耗竭机制的新信息，这对于有效的先天免疫和维持完整的肠道屏障功能至关重要。这些知识可能有助于制定新策略，以防止艾滋病毒感染者的慢性免疫激活受到损害。