阻断免疫抑制信号通路用于艾滋病功能性治愈及其对潜伏病毒储存库的作用机制研究

潜伏感染病毒储存库(LVR)是目前仍无法根治艾滋病毒(HIV)感染的关键因素。最近研究表明高水平表达免疫抑制分子(如PD-1等)的记忆CD4+T细胞是LVR重要来源，而HIV感染导致的免疫抑制和CD8+T细胞功能受损可加剧LVR的形成和维持。我们前期已证明免疫抑制阻断剂与疫苗联用可显著提升艾滋抗原特异性CD8+T细胞的免疫功能，并有效控制高剂量猴艾滋病毒(SIV)的感染，但该策略对LVR的影响及其作用机制尚不清楚。本项目对此进行系统研究，我们认为阻断免疫抑制通路可有效激活LVR，同时恢复和增强疫苗所诱发的免疫应答，二者协同作用可减少机体中的LVR，从而达到功能性治愈HIV感染之目的。将利用多种潜伏感染HIV/SIV的细胞模型及SIV感染的猕猴模型，开展一系列体内外实验进行证实，以期发现该策略调控LVR的关键机理。本研究将为优化HIV治疗策略和实现功能性治愈HIV提供重要实验数据和理论基础。

The latent viral reservoir (LVR) is the major obstacle in eradicating HIV infection. Recent studies demonstrated that memory PD-1+CD4+ T cells harbored the main source of HIV reservoir in HIV-1 patients, and the formation and maintenance of LVR was exacerbated due to activating immunoinhibitory pathway and dysfunction of CD8+ T cells by HIV infection. Our recent work showed that in vivo PD-1 blockade in combination with vaccination effectively augmented and sustained the magnitude, persistence, polyfunctionality and proliferation of SIV-specific CD8+ T cell responses and substantially improved protective efficacy against pathogenic SIVmac239 infection in rhesus monkeys. However, it is not clarified how blockade of immunoinhibitory pathway will play roles in regulating HIV latency. Therefore, we will explore this interaction and the underlying mechanism in this project. We think this strategy is promising for treating and curing chronic HIV infection, because in vivo PD-1 blockade in combination with therapeutic vaccination would not only enhance antiviral function of CD8+ T cells and immune reconstitution, but also reactivate and disrupt the latent HIV reservoir. To prove this hypothesis, we will perform a series in vitro and in vivo experiments based on a variety of latent cell model and SIV-infected monkey model, and try to find out the key mechanism in regulating LVR by this strategy. We believe this study would accumulate important experiences and provide theoretical guidance for optimizing treatment and ultimately achieving functional cure of HIV.