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Blocking type I interferon signaling to reverse T cell exhaustion and control HIV-1 reservoirs

Blocking type I interferon signaling to reverse T cell exhaustion and control HIV-1 reservoirs
阻断 I 型干扰素信号传导以逆转 T 细胞耗竭并控制 HIV-1 储存库
批准号:
10371584
负责人:
Rama Rao Amara
金额:
$53.92万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-01 至 2023-06-30

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中文摘要
翻译
项目总结 这一新项目的长期目标是阐明pDC/干扰素诱导免疫的机制。 持续HIV感染期间的抑制,并开发PDC/干扰素-I阻断新策略来控制HIV 水库。我推测,HIV激活的PDC/干扰素-I轴耗尽和损害抗HIV T细胞,以维持HIV- 1坚持不懈。因此,短暂的PDC/干扰素-I阻断将为CART免疫恢复提供新的途径。 治疗HIV-1患者,并改善CART停药后病毒反弹的控制。此外,恢复人类 在治疗性疫苗接种前短暂阻断PDC/干扰素-I的免疫也将增强疫苗的效力 控制HIV-1蓄水池。 这个项目是基于多个PI实验室在HIV感染者中的几个最新发现而提出的 人源化小鼠和SIV感染的NHP。(I)尽管PDC/干扰素-I对抑制HIV-1的急性复制至关重要 为了启动抗HIV-1 T细胞,持续感染HIV-1期间PDC的耗尽逆转了HIV-1疾病 人源化小鼠,即使在HIV-1复制增加的情况下,也拯救了抗HIV T细胞。(Ii)屏蔽 带有单抗的IFNAR还逆转了HIV感染的人源化小鼠的HIV疾病,“表型复制”PDC耗尽。 (3)在CART下感染艾滋病毒的HU小鼠中,IFNAR阻断或PDC耗尽逆转炎症,获救 人类T细胞和HIV储备库细胞减少,通过CD8依赖机制。(Iv)CD40靶向疫苗 在人源化小鼠和NHP的SIV储存库中诱导T细胞反应并减少HIV储存库。我们 假设来自持续激活的PDC的干扰素-I有助于HIV诱导的异常炎症,受损 免疫力和HIV-1持久性。该项目将阐明PDC/干扰素诱导的免疫抑制机制。 (目标1)并从功能上确定PDC/干扰素-I在抗逆转录病毒疗法(CART)期间持续存在SIV中的作用(目标2)。我们还将探索 在控制或治愈HIV-1或SIV的CART下,在治疗性疫苗接种前阻断PDC/IFNAR的想法 人源化小鼠或NHP模型中的水库(目标3)。拟议的AIMS的调查结果不仅将澄清 PDC/干扰素-I损伤宿主免疫的新机制,IFNAR阻断Bab和PDC耗尽DAb 也被开发成新的治疗方法,以1)解决艾滋病毒的异常炎症和恢复免疫活性- 1)CART患者;2)加强治疗性疫苗接种,控制CART后HIV反弹 中断(功能治愈)。
英文摘要
PROJECT SUMMARY The long-term goal of this new project is to elucidate the mechanism of pDC/IFN-induced immune suppression during persistent HIV infection, and develop novel strategy of pDC/IFN-I blockade to control HIV reservoirs. I postulate that the HIV-activated pDC/IFN-I axis depletes and impairs anti-HIV T cells to maintain HIV- 1 persistence. Thus transient pDC/IFN-I interruption will provide a novel approach of immune recovery in cART- treated HIV-1 patients and improved control of viral rebound after cART cessation. In addition, restoring human immunity by transient pDC/IFN-I interruption prior to therapeutic vaccination will also enhance vaccine efficacy to control HIV-1 reservoirs. This project is proposed based on several recent findings from the multiple PIs’ labs in HIV-infected humanized mice and in SIV-infected NHP. (i) Although pDC/IFN-I is critical to suppress acute HIV-1 replication and to prime anti-HIV T cells, depletion of pDC during persistent HIV-1 infection reverses HIV-1 diseases in humanized mice, even in the presence of elevated HIV-1 replication, and rescued anti-HIV T cells. (ii) blocking IFNAR with an mAb also reversed HIV diseases in HIV infected humanized mice, “phenocopying” pDC depletion. (iii) In HIV-infected hu-mice under cART, IFNAR blockade or pDC depletion reversed inflammation, rescued human T cells and reduced HIV+ reservoir cells, via CD8-dependent mechanism. (iv) CD40-targeting vaccines induced T cell responses and reduced HIV reservoirs in humanized mice and SIV reservoirs in NHP. We hypothesize that IFN-I from persistently activated pDC contribute to HIV-induced aberrant inflammation, impaired immunity and HIV-1 persistence. The project will elucidate mechanisms of pDC/IFN-induced immune suppression (Aim 1) and functionally define the role of pDC/IFN-I in SIV persistence during cART (Aim 2). We will also explore the idea of blocking pDC/IFNAR prior to therapeutic vaccination under cART to control or cure HIV-1 or SIV reservoirs in humanized mice or in NHP models (Aim 3). Findings from the proposed aims will not only elucidate novel mechanisms of pDC/IFN-I in impairing host immunity, the IFNAR blocking bAb and pDC depleting dAb will also be developed into novel therapeutics to 1) resolve aberrant inflammation and recover immune activity in HIV- 1 patients under cART and 2) enhance therapeutic vaccination to achieve control of HIV rebound after cART interruption (functional cure).
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