Effects of HIV SIV on unconventional T cells in immunity to M. tuberculosis in pre adolescents

项目概要 结核分枝杆菌 (Mtb) 感染是儿科人群的一个主要全球健康问题。 同时感染 HIV 和 Mtb 的儿童患结核病 (TB) 的风险会增加，即使他们是 关于抗逆转录病毒治疗。我们对艾滋病毒引起的特定免疫缺陷知之甚少 因为对 Mtb 的易感性增加，尤其是儿童。作为一种空气传播的病原体，结核分枝杆菌首先遇到的是 肺部的免疫细胞和对感染的最初反应可以决定宿主是否控制感染 或者细菌是否复制和传播，导致结核病。非常规 T 细胞，包括 CD1d- 限制性不变自然杀伤 (NK) T 细胞和粘膜相关不变 T (MAIT) 细胞，可以检测和 破坏 Mtb 感染的细胞，并可以在适应性免疫进化之前发挥作用。 HIV 会损害这两种细胞类型。在我们的 正在进行的 HIV/Mtb 双重感染研究，使用成年猕猴和 SIV 作为 HIV 替代物，我们发现 患有慢性 SIV 感染的动物更容易感染 Mtb，这与 Mtb 升高有关。 MAIT 细胞上免疫耗竭标志物（例如 PD-1）的表达。这表明 SIV 依赖 MAIT 细胞以及其他非常规 T 细胞的耗竭可能会降低对 Mtb 的抵抗力。在这里我们 将使用幼年猕猴来模拟 HIV/Mtb 双重感染儿童，并确定是否存在先前存在的 SIV 感染会损害 MAIT 和 NKT 细胞。感染 SIV 的动物将同时感染 Mtb，并且结核病进展将 可通过多种临床、放射学和病理学方法进行定量测量。我们将关联 MAIT 和 NKT 细胞的耗竭表型与结核病严重程度的关系，比较 SIV 阳性与 未接触过 SIV 的幼年猕猴。正式测试 MAIT 和 NKT 细胞的 SIV 依赖性耗竭是否会损害 结核病耐药性，我们将用抗PD-1治疗感染SIV的幼年猕猴，以逆转其免疫衰竭 MAIT 和 NKT 细胞。 Mtb 合并感染后，我们还将比较细胞和体液免疫功能 对比用抗 PD-1 治疗的动物和用对照抗体治疗的动物，结核病的严重程度。我们还将利用 缅甸仰光现有的儿科 HIV 研究 (R01MH108559) 旨在表征非常规 T 细胞 感染和未感染 HIV 以及 HIV/Mtb 合并感染的青春期前人群。我们将使用 PBMC 来 确定 HIV 和 TB 状态与外周 MAIT 和 NKT 细胞频率、免疫 疲劳状态和细胞功能。总之，这些研究将为 MAIT 的作用提供新的见解 和 NKT 细胞，以及免疫衰竭，在青春期前儿童的 HIV/Mtb 合并感染中，可能会识别 旨在改善艾滋病毒感染儿童健康结果的宿主导向疗法的目标。

Project Summary Infection with Mycobacterium tuberculosis (Mtb) is a major global health problem in pediatric populations. Children coinfected with HIV and Mtb have an increased risk of developing tuberculosis (TB), even if they are on antiretroviral therapy. We know little about the specific immune defects caused by HIV that are responsible for the increased susceptibility to Mtb, especially in children. As an airborne pathogen, Mtb first encounters immune cells in the lung and the initial response to the infection can dictate whether the host controls the infection or whether the bacteria replicate and spread, causing TB disease. Unconventional T cells, including CD1d- restricted invariant Natural Killer (NK)T cells and Mucosal-Associated Invariant T (MAIT) cells, can detect and destroy Mtb-infected cells and can act before adaptive immunity evolves. HIV impairs both cell types. In our ongoing studies of HIV/Mtb coinfection, using adult macaques and SIV as an HIV surrogate, we found that animals with chronic SIV infection are more susceptible to Mtb and that this is associated with elevated expression of immune exhaustion markers (e.g. PD-1) on MAIT cells. This suggests that SIV-dependent exhaustion of MAIT cells, and perhaps other unconventional T cells, may lower the resistance to Mtb. Here we will use juvenile macaques to model HIV/Mtb coinfected children and determine whether a preexisting SIV infection impairs MAIT and NKT cells. SIV-infected animals will be coinfected with Mtb and TB progression will be quantitatively measured by several clinical, radiologic, and pathologic methods. We will correlate the exhaustion phenotypes of MAIT and NKT cells with the severity of TB, comparing outcomes in SIV-positive vs SIV-naïve juvenile macaques. To formally test whether SIV-dependent exhaustion of MAIT and NKT cells impairs TB resistance, we will treat SIV-infected juvenile macaques with anti-PD-1 to reverse immune exhaustion of MAIT and NKT cells. Following Mtb coinfection, we will compare cellular and humoral immune function as well as TB severity in animals treated with anti-PD-1 to those treated with control antibody. We will also leverage an existing pediatric HIV study in Yangon, Myanmar (R01MH108559) to characterize unconventional T cell populations in pre-adolescents with and without HIV infection and HIV/Mtb coinfection. We will use PBMC to determine the relationship between HIV and TB status with peripheral MAIT and NKT cell frequencies, immune exhaustion status, and cellular function. Together, these studies will provide novel insights into the roles of MAIT and NKT cells, as well as immune exhaustion, in HIV/Mtb coinfection of pre-adolescent children and may identify targets for host-directed therapies aimed at improving the health outcomes of children living with HIV.