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

项目摘要 结核分枝杆菌（Mycobacterium tuberculosis，Mtb）感染是儿科人群中的主要全球性健康问题。 同时感染艾滋病毒和结核病的儿童患结核病（TB）的风险增加，即使他们是结核病 进行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， 对结核杆菌的易感性增加，尤其是在儿童中。作为一种空气传播的病原体，结核分枝杆菌首先遇到 肺中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CD 1d- 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 破坏结核杆菌感染的细胞，并能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 正在进行的HIV/Mtb共感染研究，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 MAIT细胞上免疫耗竭标志物（例如PD-1）的表达。这表明依赖SIV的 MAIT细胞以及可能其他非常规T细胞的耗竭可能降低对Mtb的抗性。这里我们 将使用青少年猕猴来模拟HIV/Mtb合并感染的儿童，并确定先前存在的SIV是否 感染损害MAIT和NKT细胞。SIV感染的动物将与结核分枝杆菌合并感染，结核病的进展将 可以通过几种临床、放射学和病理学方法进行定量测量。我们将把 MAIT和NKT细胞的耗竭表型与TB的严重程度，比较SIV阳性与 SIV-未感染幼年猕猴。为了正式测试MAIT和NKT细胞的SIV依赖性耗竭是否损害 我们将用抗PD-1抗体治疗SIV感染的幼年猕猴， MAIT和NKT细胞。在结核杆菌合并感染后，我们还将比较细胞和体液免疫功能 与用对照抗体处理的那些相比，用抗PD-1处理的动物的TB严重程度。我们还将利用 在缅甸仰光进行的现有儿科HIV研究（R 01 MH 108559），以表征非常规T细胞 有和没有艾滋病毒感染和艾滋病毒/结核病合并感染的青春期前人群。我们将使用PBMC 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，在艾滋病毒/结核病合并感染的青春期前儿童，并可能确定 这些目标旨在改善感染艾滋病毒儿童的健康结果。

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.