Re-educating T cell-mediated immunity in SIV by modulating metabolic pathways

项目摘要/摘要 艾滋病毒/艾滋病是一种慢性传染病，全世界约有3700万人受到影响。CD8 T细胞发挥重要作用 在控制艾滋病毒感染方面的关键作用。然而，随着时间的推移，CD8 T细胞会因为持续的 刺激。疲惫的HIV特异性CD8 T细胞，以抑制受体表达升高为特征 (如PD-1)，与较高的病毒载量、T细胞功能受损和疾病进展呈正相关。在艾滋病中 和其他慢性病毒感染，耗尽的抗原特异性CD8T细胞表达PD-1可以创造一个 抑制性环境表明，这种细胞不仅在疾病进展中有直接作用，而且可以 与其他免疫细胞相互干扰，损害它们的功能。慢性HIV感染使T细胞能量调节失调 新陈代谢。从感染者分离的HIV特异性CD8 T细胞显示高线粒体应激 在抗逆转录病毒治疗(ART)多年后，这一点仍然很明显。T细胞上PD-1的表达与 线粒体应激。PD-1介导的信号通过降低T细胞线粒体能量来调节T细胞能量 糖酵解和转变为脂肪酸b氧化和氧化磷酸化(OxPhos)。二甲双胍是一种 FDA批准的通过抑制线粒体复合体I来抑制OxPhos的药物。到目前为止，大多数研究 在艾滋病患者中研究二甲双胍的使用通常是在ART存在的情况下进行的。这还有待于探索它是如何 在一种天真的环境中，用二甲双胍调节能量代谢会影响宿主的免疫力。艾滋病毒不仅仅是 削弱了对病毒感染的免疫控制，但也增加了对机会性感染的易感性。人民 艾滋病毒携带者非常容易感染引起结核病的结核分枝杆菌(结核分枝杆菌)。 我们之前发现，感染SIV的毛里求斯食蟹猴(MCM)对结核分枝杆菌更敏感， 我们将其归因于先前存在的SIV感染造成的免疫损害。因此，MTB挑战是一项 对宿主防御的严格评估，鉴于艾滋病毒/结核分枝杆菌混合感染的流行率，具有很大的相关性 为了全球健康。 在这份K01提案中，我们将确定慢性HIV期间CD8T细胞能量代谢的途径 利用我们建立的HIV的MCM模型，揭示它们在T细胞耗竭中的作用。我们将使用 结合单细胞RNA测序、代谢分析和流动分析的综合分析方法 流式细胞术检测T细胞代谢在SIV感染MCM中的作用我们将使用二甲双胍改变新陈代谢 对CD8T细胞重新编程，并确定这种代谢重新编程是否通过以下方式提高宿主免疫力 用结核分枝杆菌挑战SIV动物。

Project Summary/Abstract HIV/AIDS is a chronic infectious disease that affects around 37 million people worldwide. CD8 T cells play a critical role in controlling HIV infection. However, CD8 T cells become exhausted over time due to continuous stimulation. Exhausted HIV-specific CD8 T cells, characterized by elevated expression of inhibitory receptors (e.g. PD-1), positively correlate with higher viral load, impaired T cell function, and disease progression. In HIV and other chronic viral infections, exhausted antigen-specific CD8 T cells expressing PD-1 can create a suppressive environment suggesting that such cells not only have a direct role in disease progression but can cross-talk with other immune cells to impair their function. Chronic HIV infection dysregulates T cell energy metabolism. HIV-specific CD8 T cells isolated from infected individuals exhibit elevated mitochondrial stress which is still apparent years after antiretroviral therapy (ART). PD-1 expression on T cells is associated with mitochondrial stress. PD-1-mediated signaling dysregulates T cell mitochondrial energetics by reducing glycolysis and shifting towards fatty acid b-oxidation and oxidative phosphorylation (OxPhos). Metformin is an FDA-approved drug that dampens OxPhos by inhibiting mitochondrial complex I. To date, most studies investigating metformin use in HIV+ individuals are often in the presence of ART. It has yet to be explored how modulating energy metabolism with metformin impacts host immunity in an ART-naïve setting. HIV not only impairs immune control of the viral infection, but also increases susceptibility to opportunistic infections. People living with HIV are incredibly susceptible to the tuberculosis-causing bacilli, Mycobacterium tuberculosis (Mtb). We previously showed SIV-infected Mauritian cynomolgus macaques (MCM) to be more susceptible to Mtb, which we attributed to immunologic impairment by preexisting SIV infection. Therefore, Mtb challenge is a stringent assessment of host defenses and, given the prevalence of HIV/Mtb co-infection, has great relevance to global health. In this K01 proposal, we will identify pathways involved in energy metabolism in CD8 T cells during chronic HIV infection and reveal their role in T cell exhaustion using our established MCM model of HIV. We will use a comprehensive analytic approach that combines single cell RNA sequencing, metabolic assays, and flow cytometry to assess the role of T cell metabolism in SIV-infected MCM. We will alter metabolism using metformin to reprogram CD8 T cells and determine whether this metabolic reprogramming improves host immunity by challenging SIV+ animals with Mtb.