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(Mtb)感染是儿科人群中的一个主要全球健康问题。 同时感染艾滋病毒和结核分枝杆菌的儿童患结核病的风险增加，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。 对结核杆菌的易感性增加，特别是在儿童中。作为一种空气传播的病原体，结核分枝杆菌首先遇到 肺部的免疫细胞和对感染的初始反应可以决定宿主是否控制了感染 或者细菌是否会复制和传播，从而导致结核病。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细胞(MAIT)可以检测和 摧毁感染结核分枝杆菌的细胞，并在适应性免疫进化之前采取行动。艾滋病毒对这两种细胞都有损害。在我们的 正在进行的关于艾滋病毒/结核分枝杆菌混合感染的研究，使用成年猕猴和SIV作为艾滋病毒替代品，我们发现 慢性SIV感染的动物更容易感染结核分枝杆菌，这与升高的 免疫耗竭标志物(如PD-1)在MAIT细胞上的表达。这表明依赖于SIV的 耗尽MAIT细胞，也许还有其他非常规T细胞，可能会降低对结核分枝杆菌的抵抗力。在这里我们 将使用幼年猕猴来模拟HIV/Mtb混合感染的儿童，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的动物将同时感染结核分枝杆菌和结核病进展将 通过几种临床、放射学和病理学方法进行定量测量。我们将关联 MAIT和NKT细胞耗竭表型与结核病严重程度的比较：SIV阳性与 SIV-幼稚的少年猕猴。正式测试依赖SIV的MAIT和NKT细胞衰竭是否会损害 对于结核耐药性，我们将用抗PD-1抗体治疗感染SIV的幼年猕猴，以扭转免疫衰竭 MAIT和NKT细胞。在结核分枝杆菌合并感染后，我们还将比较细胞和体液免疫功能。 经PD-1抗体处理的动物与对照抗体处理的动物相比，结核病的严重程度更高。我们还将利用 缅甸仰光现有的儿童HIV研究(R01MH108559)以表征非传统T细胞 有和没有艾滋病毒感染和艾滋病毒/结核分枝杆菌混合感染的青春期前人群。我们将使用PBMC来 确定HIV和结核病状态与外周血MAIT和NKT细胞频率、免疫的关系 疲惫状态和细胞功能。总而言之，这些研究将为MAIT的角色提供新的见解 和NKT细胞，以及免疫衰竭，在HIV/Mtb混合感染的青春期前儿童中，并可能识别 旨在改善艾滋病毒携带者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.