(PQ1) Lipid Metabolism, Inflammation, and T cell Dysfunction in HIV-associated Cancer

感染艾滋病毒的患者患多种癌症的几率更高，而且往往预后较差，尽管 有效的抗逆转录病毒治疗和癌症靶向治疗。鉴于T细胞耗尽一直很强烈 与癌症发病率和预后有关，了解慢性、持续性 炎症和T细胞功能障碍是艾滋病毒患者发展为癌症的关键。我们的预赛 小鼠的数据显示，暴露在脂肪酸环境中会促进T细胞耗竭的特性(如增加 PD-1表达和抑制效应器功能)。我们还发现，游离脂肪酸(FFAs)水平 与健康对照组相比，慢性病毒感染和黑色素瘤模型的小鼠显著升高，2 存在功能耗尽的PD-1hi T细胞的设置。根据这些数据和初步数据 在HIV感染者中，我们认为脂质失调的存在和持续导致了一种 直接导致T细胞功能障碍和PD-1增加的积极促炎环境 表情。艾滋病毒感染者中由于病毒感染和代谢综合征的高发生率 抗逆转录病毒治疗本身，进一步导致炎症和T细胞功能障碍。因此，我们将探索 HIV感染者的血脂紊乱与T细胞衰竭是否有直接关系 以及耗尽的T细胞的存在是否会导致该人群癌症发病率的增加。通过 利用建立良好的纵向队列，我们处于一个独特的位置来解决免疫的作用 HIV感染者中癌症发病率增加与功能障碍和脂代谢的关系。在……里面 此外，我们将使用HIV感染的受试者样本和慢性病毒感染的小鼠模型来 确定循环FFA和脂肪酸摄取升高对T细胞衰竭的影响。我们的目标将是(1) 在HIV感染者中建立脂质失调和T细胞耗竭之间的联系，在HIV- 罹患癌症的感染者，以及来自艾滋病毒感染者的肿瘤组织；(2)定义 通过CD36等转运蛋白摄取游离脂肪酸影响T细胞功能障碍的机制 慢性感染的小鼠模型，癌症的小鼠模型，以及艾滋病毒感染者的模型；理解 代谢综合征和免疫抑制肿瘤环境之间的炎症联系是重要的 发现预防和/或治疗癌症的新靶点，其中可能包括针对脂肪酸的干预 发信号。

Patients with HIV infection have higher incidence of many cancers and often with a poorer prognosis, despite effective antiretroviral therapy and cancer-targeted therapy. Given that T cell exhaustion has been strongly implicated in cancer incidence and outcome, understanding the connection between chronic, persistent inflammation and T cell dysfunction is critical among patients with HIV who develop cancer. Our preliminary murine data shows that exposure to fatty acids promotes properties of T cell exhaustion (such as increased PD-1 expression and suppression of effector functions). We also find that free fatty acids (FFAs) levels are significantly higher in murine models of chronic viral infection and melanoma compared to healthy controls, two settings in which functionally exhausted PD-1hi T cells are present. Based on these data and preliminary data in HIV infected individuals, we propose that the presence and persistence of lipid dysregulation results in an aggressively pro-inflammatory environment that directly contributes T cell dysfunction and increased PD-1 expression. The high rate of metabolic syndrome among HIV-infected individuals, due to viral infection and antiretroviral therapy itself, further contributes to inflammation and T cell dysfunction. We will thus explore whether there is a direct correlation between lipid dysregulation and T cell exhaustion in HIV-infected patients and whether presence of exhausted T cells results in increased cancer incidence in this population. By utilizing a well-established longitudinal cohort, we are in a unique position to address the role of immune dysfunction and lipid metabolism upon increased cancer incidence among HIV-infected individuals. In addition, we will use both HIV-infected subject samples and a murine model of chronic viral infection to determine the impact of elevated circulating FFA and fatty acid uptake on T cell exhaustion. Our aims will (1) establish a link between lipid dysregulation and T cell exhaustion in HIV-infected individuals, among HIV- infected individuals who develop cancer, and in tumor tissue from HIV-infected individuals; (2) define the mechanism by which free fatty acid (FFA) uptake, via transporters such as CD36, impacts T cell dysfunction in a murine model of chronic infection, a murine model of cancer, and in HIV-infected individuals; Understanding the inflammatory link between metabolic syndromes and immunosuppressive tumor environment is important to discover new targets to prevent and/or treat cancer, which may include interventions targeting fatty acid signaling.