Role of persistent type I IFN signaling in immune suppression and tumorigenesis during chronic HIV infection

项目摘要 HIV是一种炎症和慢性免疫激活疾病。最终，这会导致严重的免疫缺陷。 功能障碍和其他合并症的发生，包括癌症。在艾滋病中， 潜在的慢性炎症以及它们如何导致免疫恶化和癌症风险增加 疾病以及治疗干扰这一过程的能力是否可以恢复免疫功能。 权限尚不明确。在多个物种中，包括慢性病毒感染的小鼠模型， 在灵长类动物中的感染，以及人类中的HIV感染，越来越多的证据表明I型干扰素（IFN-I） 信号传导作为慢性炎症的核心机制， 抑制免疫环境促进癌症生长。本提案的目的是阐明 慢性IFN-I信号传导、炎症、免疫衰竭和肿瘤发生之间的关系 免疫抑制肿瘤小生境有利于肿瘤生长。 为了实现这一目标，我们将利用人源化小鼠模型，其1）允许移植物的植入和生长， 多种肿瘤细胞系和2）重现IFN-Ⅰ诱导的免疫激活和慢性HIV期间的耗竭 体内感染。我们将利用新的策略来促进或阻断体内IFN-I信号传导，并建立一种创新的 特异性产生肿瘤特异性T细胞的方法：（1）确定IFN-1信号传导的精确贡献 在HIV感染过程中，免疫抑制肿瘤的发展环境和抗肿瘤药物的耗竭 研究在慢性HIV感染过程中阻断慢性IFN-1信号传导是否能促进肿瘤生长 可提高抗肿瘤免疫力和免疫检查点抑制剂阻断的功效。 一旦完成，我们强烈认为，我们的研究将大大促进对 导致免疫功能障碍和艾滋病风险增加的基本机制和非艾滋病相关的 癌这也将为未来的研究提供基础，理论基础和系统，以定义和治疗 靶向炎症和免疫激活用于HIV感染癌症治疗。

Project Summary HIV is a disease of inflammation and chronic immune activation. Ultimately, this results in severe immune dysfunctions and occurrence of other comorbidities, including cancer. In HIV disease, the mechanisms underlying chronic inflammation and how they contribute to immune deterioration and increased risk in cancer diseases as well as whether the ability to therapeutically interfere with this process could restore immune competence remain unclear. Across multiple species, including mouse models of chronic virus infection, SIV infection in primates, and HIV infection in humans, mounting evidence implicates type I interferon (IFN-I) signaling as a central mechanism underlying the chronic inflammation that drives the development of suppressive immune environment that promote cancer growth. The goal of this proposal is to elucidate the relationship between chronic IFN-I signaling, inflammation, immune exhaustion, and the development of an immuno-suppressive tumor niche that favors tumor growth. To achieve this goal, we will utilize a humanized mouse model that 1) allows engraftment and growth of multiple tumor cell lines and 2) recapitulates IFN-I induced immune activation and exhaustion during chronic HIV infection in vivo. We will utilize novel strategies to promote or block IFN-I signaling in vivo and an innovative approach to specifically generate tumor specific T cells to: (1) define the precise contribution of IFN-I signaling during HIV infection to the development of immuno-suppressive tumor enviroment and exhaustion of anti-tumor T cell that favor cancer growth; and (2) investigate if blocking chronic IFN-I signaling during chronic HIV infection can improve anti-tumor immunity and efficacy of immune checkpoint inhibitor blockade. Once completed, we strongly feel that our studies will significantly advance the understanding of the fundamental mechanisms that result in immune dysfunction and increased risk of AIDS and non-AIDS-related cancer. This will also provide the foundation, rationale, and system for future studies to define and therapeutically target inflammation and immune activation for cancer treatment with HIV infection.