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）感染者的主要死因。大多数感染结核分枝杆菌（Mtb）的HIV阴性个体无症状，并被认为具有潜伏性结核感染（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HIV共感染时，LTBI个体的一个子集进展为临床活动性TB疾病。这是由于LTBI的重新激活，可能是由于Mtb在体内失去控制。 肺肉芽肿性病变。抗原特异性T细胞对于控制人类和实验动物模型中的Mtb感染至关重要，并且HIV感染后CD 4 T细胞计数的降低大大增加了患TB的风险。然而，Mtb特异性T细胞应答维持LTBI、赋予保护性免疫或导致HIV诱导的LTBI再活化的机制仍不清楚。为了开发用于HIV高流行人群的有效TB疫苗并有效治疗Mtb/HIV共感染，我们迫切需要了解HIV如何干扰灵长类免疫系统对慢性状态下Mtb感染的潜伏控制。我们假设，与HIV共感染耗尽和/或损害结核分枝杆菌特异性CD 4和CD 8 T细胞的功能能力，以驱动LTBI的再激活，抗逆转录病毒治疗（ART）只能部分恢复这些功能。我们建议在吸入性肺结核的高度人样非人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i）定义与LTBI印度恒河猴肺、支气管肺泡灌洗和外周血中Mtb感染的免疫控制相关的Mtb特异性CD 4和CD 8 T细胞反应的性质; ii）测试以下假设：与SIVmac 239联合感染逐渐损害Mtb特异性CD 4和CD 8 T细胞功能，导致LTBI重新激活;和iii）检查抗逆转录病毒疗法对Mtb/SIV共感染的NHP中Mt特异性CD 4和CD 8 T细胞应答重建的影响。

 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.