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的疾病。最终，这会导致严重的免疫 功能障碍和其他合并症的发生，包括癌症。在艾滋病毒疾病中，机制 潜在的慢性炎症及其如何导致免疫恶化和癌症风险增加 以及通过治疗干预这一过程的能力是否可以恢复免疫力 能力仍不明朗。跨多种物种，包括慢性病毒感染的小鼠模型，SIV 灵长类动物感染和人类艾滋病毒感染，越来越多的证据表明与I型干扰素(干扰素-I)有关 信号是慢性炎症的核心机制，慢性炎症推动了 促进癌症生长的抑制性免疫环境。这项提议的目的是澄清 慢性干扰素-I信号、炎症、免疫衰竭与AN发生发展的关系 有利于肿瘤生长的免疫抑制肿瘤利基。 为了实现这一目标，我们将利用人性化的老鼠模型，1)允许嫁接和生长 多个肿瘤细胞株和2)重述干扰素-I在慢性HIV中诱导的免疫激活和耗竭 体内感染。我们将利用新的策略来促进或阻止体内的干扰素-I信号和创新的 特异性产生肿瘤特异性T细胞的方法：(1)确定干扰素-I信号的精确作用 HIV感染过程中免疫抑制肿瘤环境的发展及抗肿瘤作用的耗竭 促进肿瘤生长的T细胞；以及(2)研究在慢性HIV感染期间是否阻断慢性干扰素-I信号 可提高抗肿瘤免疫和免疫检查点抑制剂阻断的疗效。 一旦完成，我们强烈地感觉到我们的研究将大大促进对 导致免疫功能障碍和增加艾滋病和非艾滋病相关风险的基本机制 癌症。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 针对HIV感染的癌症治疗的炎症和免疫激活。

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.