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

项目摘要 本项目的长期目标是阐明pDC/IFN诱导免疫的机制， 在持续HIV感染期间抑制，并开发新的pDC/IFN-I阻断策略来控制HIV 水库我假设HIV激活的pDC/IFN-I轴消耗并损害抗HIV T细胞以维持HIV-1。 1坚持。因此，瞬时pDC/IFN-I中断将提供cART中免疫恢复的新方法。 治疗HIV-1患者，并改善cART停止后病毒反弹的控制。此外，恢复人类 在治疗性疫苗接种之前通过瞬时pDC/IFN-1中断的免疫也将增强疫苗效力， 控制HIV-1病毒库。 该项目是根据多个PI实验室在HIV感染者中的几项最新发现提出的。 在人源化小鼠和SIV感染的NHP中。(i)尽管pDC/IFN-I对于抑制急性HIV-1复制至关重要， 并引发抗HIV T细胞，在持续HIV-1感染期间消耗pDC逆转HIV-1疾病， 人源化小鼠，即使在存在升高的HIV-1复制的情况下，也能拯救抗HIV T细胞。(ii)阻挡 IFNAR与mAb还逆转了HIV感染的人源化小鼠中的HIV疾病，“表型复制”pDC消耗。 (iii)在接受cART治疗的HIV感染的hu小鼠中，IFNAR阻断或pDC耗竭逆转了炎症，挽救了细胞凋亡。 人T细胞和减少的HIV+储库细胞，通过CD 8依赖性机制。(iv)CD 40靶向疫苗 诱导T细胞应答，并减少人源化小鼠中的HIV储库和NHP中的SIV储库。我们 假设来自持续活化pDC的IFN-I有助于HIV诱导的异常炎症、受损 免疫力和HIV-1持久性。本项目将阐明pDC/IFN诱导的免疫抑制机制 (Aim 1）并在功能上定义pDC/IFN-I在cART期间SIV持续性中的作用（目的2）。我们还将探索 在cART下的治疗性疫苗接种之前阻断pDC/IFNAR以控制或治愈HIV-1或SIV的想法 在人源化小鼠中或在NHP模型中的储库（Aim 3）。从拟议目标中得出的结果不仅将阐明 pDC/IFN-I在损害宿主免疫中的新机制，IFNAR阻断性bAb和pDC消耗性dAb将 也被开发成新的治疗剂，以1）解决异常炎症和恢复HIV中的免疫活性， 1例患者接受cART治疗，2）加强治疗性疫苗接种，以控制cART后的HIV反弹 功能治疗（functional cure）。

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).