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

HIV感染者的免疫系统无法消除重新激活后的潜伏感染细胞， 导致停止抗逆转录病毒治疗后病毒血症复发，阻碍功能性治愈。这个 HIV 感染者 (PWH) 需要终身接受 ART。需要新的策略来调动免疫系统 防止 ART 停止后 HIV 病毒库中出现 HIV。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) 能够传递抗原特异性 TCR 信号和配体 定义的共刺激信号。我们证明了 synTacs 带有 CMV 衍生肽和抗 CD28 scFv 或 4-1BBL 信号模块，刺激剧烈且选择性的离体和体内高度扩增 PWH PBMC 中的多功能 CMV 特异性 CD8 T 细胞，显示出有效的体内抗 CMV 活性。我们 最近还描述了 CAR-T 细胞的有效体外和体内抗 HIV 活性，该细胞使用新型两种 分子 duoCAR 架构可共表达两个独立的 CAR，每个 CAR 识别不同的 gp120 表位。 HIV 特异性 T 细胞反应或 CAR-T 细胞治疗无法持续控制 HIV 感染，因为 即使在没有突变免疫的情况下，其功能性抗艾滋病毒活性最终也会减少或丧失 逃脱。相比之下，CMV 特异性 T 细胞反应由效应记忆 CD8 T 细胞组成，这些细胞维持其 细胞因子释放、杀伤和增殖的能力，并且实际上随着时间的推移而扩展，这种表型被描述为 记忆膨胀。我们假设结合 synTacs 的能力来激活和显着扩展 CMV- 特定的 CD8 T 细胞具有新的策略来重定向它们以消除 HIV 感染的细胞，将利用高度 功能性且有弹性的 CMV 特异性 CD8 T 细胞反应，可改善 HIV 感染的免疫控制。 我们建议结合 synTacs 的能力来选择性激活和显着扩展 CMV 特异性 CD8 T 细胞具有有效且持续的抗病毒活性，具有三个特定目标 (SA)，可将其重定向至 HIV- 被感染的细胞。我们将扩增的 CMV CD8 T 细胞转化为 HIV 特异性 CAR T 细胞 (SA 1)，或者 抗 HIV T 细胞 (SA 2)，或修改 synTac 结构以连接 CMV-c-pMHC、gp120-结合剂和共刺激 配体，完全激活并引导 CMV CD8 T 细胞靶向 HIV 感染细胞 (SA 3)，从而动员 体内免疫反应可控制 HIV 感染，消除重新激活的潜伏感染细胞，并提供 艾滋病毒感染者的艾滋病毒感染持续无抗逆转录病毒治疗缓解。此外，我们还将利用 synTacs 交付 定义共刺激信号，以扩展我们对不同共刺激信号能力的了解 产生最有效的 CD8 T 细胞和 CAR-T 细胞，以消除重新激活的潜伏感染 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.