Amplifying and Redirecting CMV-specific CD8 T cells to provide sustained control of HIV infection

HIV感染者的免疫系统在重新激活后不能消除潜伏感染的细胞， 导致停止抗逆转录病毒治疗后病毒血症复发，妨碍功能性治愈。这 艾滋病毒感染者（PWH）需要终身抗逆转录病毒治疗。需要新的策略来调动免疫系统 防止ART停止后艾滋病毒从艾滋病毒库中出现。我们最近开发了synTacs， 由连接MHC分子的二聚Fc结构域支架组成的可输注免疫刺激生物制剂， 病毒衍生肽（c-pMHC），其能够递送抗原特异性TCR信号和配体， 明确的共刺激信号。我们证明了携带CMV衍生肽和抗CD 28的synTac scFv或4-1BBL信号传导模块，刺激了高度增殖的细胞的强有力的和选择性的离体和体内扩增。 在PWH PBMC中的多功能CMV特异性CD 8 + T细胞，其显示出有效的体内抗CMV活性。我们 最近也描述了CAR-T细胞的有效的体外和体内抗HIV活性，其使用新的双- 分子duoCAR架构以共表达两个独立的汽车，每个识别不同的gpl 20表位。 HIV特异性T细胞应答或CAR-T细胞治疗无法持续控制HIV感染， 即使在没有突变免疫的情况下， 逃跑相比之下，CMV特异性T细胞应答由维持其免疫应答的效应记忆CD 8 T细胞组成。 细胞因子释放，杀伤和增殖的能力，并实际上随着时间的推移而扩大，这种表型被描述为 记忆膨胀我们假设，结合synTacs激活和显著扩增CMV的能力， 特异性CD 8 T细胞与新的策略，以重新引导他们消除艾滋病毒感染的细胞，将利用高度 功能性和弹性CMV特异性CD 8 T细胞应答，以提供改善的HIV感染免疫控制。 我们建议联合收割机结合synTacs选择性激活和显著扩增CMV特异性CD 8 T细胞具有有效和持续的抗病毒活性，具有三种特异性目的（SA），可将其重定向至靶向HIV-1。 被感染的细胞我们将扩增的CMV CD 8 T细胞转化为HIV特异性CAR T细胞（SA 1），或 抗HIV T细胞（SA 2），或修饰synTac结构以连接CMV-c-pMHC、gp 120结合剂和共刺激细胞 配体，以完全激活并指导CMV CD 8 T细胞靶向HIV感染的细胞（SA 3），从而动员 一种体内免疫反应，控制HIV感染，消除重新激活的潜伏感染细胞， 在威尔斯亲王医院接受持续无抗逆转录病毒疗法的HIV感染缓解。此外，我们还将利用synTacs提供 定义的共刺激信号，以扩展我们关于不同共刺激信号的能力的知识 以产生最有效的CD 8 + T细胞和CAR-T细胞，用于消除再活化的潜伏感染的T细胞。

The immune system of HIV-infected individuals is unable to eliminate latently infected cells following reactivation, resulting in the recurrence of viremia after stopping antiretroviral therapy, preventing functional cure. This necessitates lifelong ART for people with HIV (PWH). New strategies are needed to mobilize the immune system to prevent the emergence of HIV from the HIV reservoir after ART cessation. We recently developed synTacs, infusible immunostimulatory biologics consisting of dimeric Fc-domain scaffolds linking MHC molecules and virus-derived peptides (c-pMHC) capable of delivering antigen-specific TCR-signals and ligands that supply defined costimulatory signals. We demonstrated that synTacs bearing CMV-derived peptides, and anti-CD28 scFv or 4-1BBL signaling modules, stimulated vigorous and selective ex vivo and in vivo expansion of highly polyfunctional CMV-specific CD8+ T cells in PWH PBMC, which displayed potent in vivo anti-CMV activities. We also recently described the potent in vitro and in vivo anti-HIV activity of CAR-T cells that use a novel two- molecule duoCAR architecture to co-express two independent CARs, each recognizing a distinct gp120 epitope. HIV-specific T cell responses or CAR-T cell treatments fail to provide sustained control of HIV infection because of the eventual reduction or loss of their functional anti-HIV activity, even in the absence of mutational immune escape. In contrast, CMV-specific T cell responses consist of effector memory CD8 T cells that maintain their capacity for cytokine release, killing and proliferation and actually expand over time, a phenotype described as memory inflation. We hypothesize that combining the capacity of synTacs to activate and markedly expand CMV- specific CD8 T cells with novel strategies to redirect them to eliminate HIV-infected cells, would exploit the highly functional and resilient CMV-specific CD8 T cell responses to provide improved immune control of HIV infection. We propose to combine the capacity of synTacs to selectively activate and markedly expand CMV-specific CD8 T cells with potent and sustained anti-viral activity with three Specific Aims (SA) to redirect them to target HIV- infected cells. We will either convert the expanded CMV CD8 T cells into HIV-specific CAR T cells (SA 1), or anti-HIV T cells (SA 2), or modify the synTac structure to link CMV-c-pMHC, gp120-binders and costimulatory ligands, to both fully activate and direct CMV CD8 T cells to target HIV-infected cells (SA 3), thereby mobilizing an in vivo immune response that controls HIV infection, eliminates reactivated latently infected cells and provides sustained ART-free remission of HIV infection to PWH. Furthermore, we will also utilize synTacs delivering defined costimulatory signals, to extend our knowledge regarding the capacity of different costimulatory signals to generate the most potent CD8+ T cells and CAR-T cells for eliminating reactivated latently infected T cells.