Designing T cells to Functionally Cure HIV-1 infection

项目3：摘要 CD4T细胞在协调免疫应答方面起着关键作用，并发挥着重要作用 控制和消除病毒感染。由于HIV-1对CD4T细胞的趋向性，尤其是 HIV-1特异性的CD4T细胞，对对抗HIV-1感染的CD4T细胞的反应是受损的。 这个项目的基本目标是开发一种策略，可以恢复完整的CD4T细胞 与艾滋病毒-1感染作斗争的活动。在项目2中，我们将使用最多的 保护CD4T细胞免受HIV-1感染的有效方法。接下来，我们将检查哪个CD4T细胞 细胞亚群和哪个嵌合抗原受体最能恢复持久的HIV-1特异性活性 CD4T细胞。我们将与项目4密切合作，确定控制可持续发展的关键因素 以及CD4T细胞的功能。然后利用这些信息，我们将进一步提炼我们的基因 提高抗HIV-1CD4T细胞活性的工程策略。在目标3中，我们将模拟采用 使用人源化小鼠进行的T细胞试验，以确定哪种工程组合提供了 最有效和持久地控制艾滋病毒-1复制。这些研究将提供基础和 在项目1中描述的研究之后进行临床试验的基本原理。 SA1：确定最佳的CD4CAR共刺激结构域和细胞类型以提供耐受性 HIV-1体外感染的控制。 SA2：确定最佳的CD4CAR共刺激结构域和细胞类型，提供 最有助于HIV-1特异性的CD8 T细胞。 SA3：研究受保护的HIV-1特异性T细胞能否在功能上控制 HIV-1在体内复制。。

PROJECT 3: ABSTRACT CD4 T cells play a key role orchestrating the immune response and play an important role controlling and eliminating viral infections. Due to HIV-1 tropism for CD4 T cells and especially HIV-1 specific CD4 T cells, the CD4 T cell response to combat HIV-1 infection is compromised. The underlying goal of this project is to develop a strategy that would restore full CD4 T cell activity to fight against HIV-1 infection. Working with Project 2, we will employ the most effective way to protect CD4 T cells from HIV-1 infection. Next, we will examine which CD4 T cell subset and which chimeric antigen receptor best restores durable HIV-1 specific activity to CD4 T cells. We will work closely with Project 4 to define the key factors that control the durably and functionality of CD4 T cells. Then using this information we will further refine our gene engineering strategy to enhance anti-HIV-1 CD4 T cell activity. In aim 3 we will model adoptive T cell trials using humanized mice to determine which combination of engineered provide the most effective and durable control of HIV-1 replication. These studies will provide the basis and rationale for a clinical trial that will follow the study described in Project 1. SA1: To identify the optimal CD4 CAR costimulatory domain and cell type to give durable control of HIV-1 infection in vitro. SA2: To identify the optimal CD4 CAR costimulatory domain and cell type that provides the most help to HIV-1 specific CD8 T cells. SA3: To investigate whether protected HIV-1 specific T cells can functionally control HIV-1 replication in vivo. .