Targeting Type I Interferon Immune Activation to Control HIV Infection in vivo

产品说明：免疫激活和HIV疾病进展密切相关，这表明干扰持续刺激免疫反应的因素可能具有巨大的治疗益处。然而，免疫激活背后的确切机制，它如何导致免疫恶化，治疗干扰这一过程的能力，以及阻断免疫激活是否可以恢复免疫能力都不清楚。因此，有许多关键的问题，必须解决之前，这一潜在的重要的治疗策略可以有效地实施。在多个物种中，包括慢性病毒感染的小鼠模型，灵长类动物中的SIV感染和人类中的HIV感染，越来越多的证据表明慢性I型干扰素（IFN-I）信号传导是驱动免疫激活，功能障碍和最终病毒持续存在和疾病进展的中心机制。该提案的目标是了解慢性IFN-I信号传导，免疫激活和HIV感染期间免疫功能障碍之间的关系，并实施抑制IFN-I信号传导以恢复免疫功能和控制HIV感染的治疗策略。为了实现这一目标，我们将利用在体内重现IFN-Ⅰ诱导的免疫激活的人源化小鼠和特异性产生HIV特异性T细胞的创新方法：（1）确定HIV感染期间IFN-Ⅰ介导的免疫激活和功能障碍的精确靶点;（2）在体内抑制IFN-Ⅰ以逆转慢性免疫激活并增强HIV特异性T细胞免疫;和（3）确定阻断IFN-1的病毒学影响。一旦完成，我们的研究将大大推进我们对HIV的理解：增强病毒持久性的免疫相互作用，并为未来研究定义和靶向HIV感染期间的免疫激活提供基础、原理和系统。

DESCRIPTION: Immune activation and HIV disease progression are tightly linked, suggesting that interfering with the factors that continually stimulate the immune response could have tremendous therapeutic benefit. Yet, the precise mechanisms underlying immune activation, how it contributes to immune deterioration, the ability to therapeutically interfere with this process, and whether blocking immune activation could restore immune competence are all unclear. Thus, there are many critical questions that must be addressed before this potentially important therapeutic strategy can be effectively implemented. Across multiple species, including mouse models of chronic virus infection, SIV infection in primates, and HIV infection in humans, mounting evidence implicates chronic type I interferon (IFN-I) signaling as a central mechanism driving immune activation, dysfunction, and ultimately viral persistence and disease progression. The goal of this proposal is to understand the relationship between chronic IFN-I signaling, immune activation, and immune dysfunction during HIV infection and implement a therapeutic strategy to inhibit IFN-I signaling to restore immune function and control HIV infection. To achieve this goal, we will utilize humanized mice that recapitulate IFN-I induced immune activation in vivo and an innovative approach to specifically generate HIV-specific T cells to: (1) define the precise IFN-I mediated targets of immune activation and dysfunction during HIV infection; (2) inhibit IFN-I in vivo to reverse chronic immune activation and enhance HIV-specific T cell immunity; and (3) determine the virologic impact of blocking IFN-I. Once completed, our studies will significantly advance our understanding of HIV:immune interactions that potentiate viral persistence and provide the foundation, rationale, and system for future studies to define and target immune activation during HIV infection.