Perturbation of antigen-specific T cell responses in latent TB/SIV co-infection

 描述(由申请人提供)： 结核病(TB)是全球人类免疫缺陷病毒(HIV)感染者的主要死亡原因。大多数感染结核分枝杆菌(Mtb)的HIV阴性个体没有症状，被认为患有潜伏性结核病感染(LTBI)，这为宿主免疫控制感染提供了令人信服的证据。然而，当与艾滋病毒共同感染时，部分LTBI患者进展为临床活动性结核病。这是由于LTBI重新激活造成的，可能是由于失去了对MTB的控制 肺肉芽肿性病变。在人类和实验动物模型中，抗原特异性T细胞对控制结核分枝杆菌感染至关重要，艾滋病毒感染后CD4T细胞数量的减少极大地增加了患结核病的风险。然而，结核分枝杆菌特异性T细胞反应维持LTBI、提供保护性免疫或导致HIV诱导的LTBI重新激活的机制仍不清楚。要为HIV高流行率人群开发有效的结核病疫苗并有效治疗结核分枝杆菌/艾滋病毒混合感染，我们迫切需要了解HIV如何扰乱灵长类动物免疫系统在慢性状态下对结核分枝杆菌感染的潜在控制。我们假设，与HIV混合感染会耗尽和/或损害结核分枝杆菌特异性CD4和CD8T细胞驱动LTBI重新激活的功能能力，而抗逆转录病毒疗法(ART)只能部分恢复这些功能。我们建议在吸入性结核病的高度类似人类的非人类灵长类动物模型中使用机械实验来验证这一假设。为了实现这一目标，我们将：1)确定与结核分枝杆菌感染的免疫控制有关的结核分枝杆菌特异性CD4和CD8 T细胞反应的性质；2)检验SIVmac239合并感染会逐渐损害结核分枝杆菌特异性CD4和CD8 T细胞功能，导致LTBI重新激活的假说；以及3)研究抗逆转录病毒治疗对结核分枝杆菌/SIV混合感染的NHP中结核分枝杆菌特异性CD4和CD8 T细胞反应重建的影响。

 DESCRIPTION (provided by applicant): Tuberculosis (TB) is the leading cause of death in Human Immunodeficiency Virus (HIV)-infected individuals globally. The majority of HIV-negative individuals infected with Mycobacterium tuberculosis (Mtb) are asymptomatic, and are considered to have latent TB infection (LTBI), providing compelling evidence for host immune control of infection. However, a subset of individuals with LTBI progress to clinically active TB disease when co-infected with HIV. This results from the reactivation of LTBI, potentially due to a loss of control of Mtb within pulmonary granulomatous lesions. Antigen-specific T cells are crucial for controlling Mtb infection in humans and in experimental animal models and lowering of CD4 T cell counts after HIV infection greatly increases the risk of developing TB. However, the mechanisms by which Mtb-specific T cell responses maintain LTBI, confer protective immunity or result in HIV-induced reactivation of LTBI, remain unclear. To develop an effective TB vaccine for populations with high HIV prevalence and to effectively treat Mtb/HIV co- infection, we urgently need to understand how HIV perturbs the latent control of Mtb infection in a chronic state by the primate immune system. We hypothesize that co-infection with HIV depletes and/or impairs in the functional capacities of Mtb-specific CD4 and CD8 T cells to drive reactivation of LTBI and that antiretroviral therapy (ART) only partially restores these functions. We propose to test this hypothesis using mechanistic experiments in the highly human-like nonhuman primate model of inhalation TB. Towards this goal we will i) Define the nature of Mtb-specific CD4 and CD8 T cell responses associated with immune control of Mtb infection in the lungs, BAL and peripheral blood of Indian rhesus macaques with LTBI; ii) Test the hypothesis that co-infection with SIVmac239 progressively impairs Mtb-specific CD4 and CD8 T cell functions, leading to reactivation of LTBI; and iii) Examine the effect of antiretroviral therapy on reconstitution of Mt-specific CD4 and CD8 T cell responses in Mtb/SIV co-infected NHPs.