Immunity to TB in highly immunosuppressed HIV-infected and uninfected individuals

虽然感染结核分枝杆菌是导致肺部疾病和死亡的最大原因 在全球艾滋病毒患者中，结核病合并感染对长期抗逆转录病毒(ART)的影响知之甚少。 介导的免疫重建。柬埔寨早期抗逆转录病毒药物与晚期抗逆转录病毒药物(Camelia) 随机临床试验表明，在结核病治疗开始后2周，早期开始抗逆转录病毒治疗比晚期开始 免疫功能严重受损的TB+/HIV+患者在8周开始抗逆转录病毒治疗(中位数CD4=24/mm3)， 导致死亡率显著下降(34%)--这一生存优势至少持续了3年 时机上的干预。在一项嵌套在Camelia试验中的科学子研究中，我们发现 这些高度免疫抑制的TB+/HIV+患者中的活动性结核病导致显著更多的抗逆转录病毒治疗前 几种促炎细胞因子水平和术前活化的CD4+和CD8+T细胞频率升高 细胞，CD28+CD8+和ICOS+CD4+T细胞在ART前的频率明显低于 结核病/艾滋病毒阳性患者。此外，T细胞亚群频率的这些差异至少持续了8个月 治疗开始后和结核病治愈后2个月。此外，我们已经证明了与结核病相关的 免疫重建综合征(TB-IRIS)，发病率是骆驼早期的2.6倍 治疗臂，导致T细胞室的深刻变化。例如，结核病-IRIS患者 表现出术后(CD62L-CD45RA-)效应记忆CD4+T细胞显著扩张和减少 (CD62L+CD45RA-)中枢记忆中的CD4+T细胞与非TB-IRIS患者的比较。我们还发现了 一种类似Th1的CD4+T细胞亚群，即CXCR3+CCR6+，被认为介导了很大一部分抗结核 在接受抗逆转录病毒治疗前，TB-IRIS患者的反应频率显著升高， 这些细胞在治疗开始后至少8个月内保持升高。根据我们的初步数据，我们 假设结核合并感染会加剧艾滋病毒引起的免疫系统过早老化，导致 长期后果和糟糕的召回反应。在目标1中，我们将研究免疫致敏和 TB+/HIV+骆驼和TB-/HIV+和TB+治疗前存档样本中的甲基组特征 /HIV患者，以及在结核病治疗和抗逆转录病毒治疗5年后从相同患者身上新分离的样本。 入会仪式。我们进一步假设，在TB+/HIV+组中，经历过结核病的患者子集- 虹膜具有较高的抗结核分枝杆菌免疫力，在ART启动后，这种免疫力被放大。在《目标2》中我们将 比较TB-IRIS患者与非TB-IRIS患者CXCR3+CCR6+CD4+T细胞抗结核分枝杆菌抗体 功能。这些实验的发现将为HIV+患者中结核病合并感染提供关键的见解 影响ART免疫前后免疫系统的表型和表观遗传特征 重建，他们将阐明TB-IRIS对功能MTB特异性T细胞的长期后果 与ART介导的免疫重建和结核病治愈相关的反应。

Although infection with Mycobacterium tuberculosis (MTb) is the largest cause of pulmonary disease and death in HIV patients globally, little is known about how TB co-infection impacts long-term antiretroviral (ART)- mediated immune reconstitution. The Cambodian Early vs. Late Introduction of Antiretrovirals (CAMELIA) randomized clinical trial showed that early initiation of ART at 2 weeks after TB therapy initiation versus late initiation of ART at 8 weeks in severely immunocompromised TB+/HIV+ patients (median CD4=24/mm3), resulted in a significant (34%) decrease in mortality—a survival benefit that persisted for at least 3 years after the timing intervention. In a scientific sub-study nested within the CAMELIA trial, we have discovered that active TB disease in these highly immunosuppressed TB+/HIV+ patients led to significantly greater pre-ART levels of several pro-inflammatory cytokines and greater pre-ART frequencies of activated CD4+ and CD8+ T cells, and significantly lower pre-ART frequencies of CD28+CD8+ and ICOS+CD4+ T cells, as compared to TB-/HIV+ patients. Moreover, these differences in T cell subset frequencies persisted for at least 8 months after treatment initiation and 2 months after TB cure. Furthermore, we have demonstrated that TB-associated immune reconstitution syndrome (TB-IRIS), which occurred 2.6-fold more frequently in the early CAMELIA treatment arm, results in profound changes in the T cell compartment. For example, TB-IRIS patients exhibited a significant post-ART expansion of (CD62L-CD45RA-) effector memory CD4+T cells and a decrease in (CD62L+CD45RA-) central memory CD4+T cells as compared to non-TB-IRIS patients. We have also found that a Th1-like CD4+ T cell subset that is CXCR3+CCR6+ and thought to mediate a large portion of anti-TB responses was present at significantly elevated frequencies pre-ART in TB-IRIS patients, and the frequency of these cells remained elevated for at least 8 months after treatment onset. Based on our preliminary data, we hypothesize that TB co-infection exacerbates HIV-induced premature aging of the immune system, leading to long-term consequences and poor recall responses. In Aim 1 we will investigate immunosenescent and methylomic signatures in pre-treatment archived samples from TB+/HIV+ CAMELIA and TB-/HIV+ and TB+ /HIV- patients, and in freshly isolated samples from the same patients >5 years after TB treatment and ART initiation. We further hypothesize that within the TB+/HIV+ group the subset of patients who experienced TB- IRIS possessed superior anti-MTb immunity, which was amplified once ART was initiated. In Aim 2 we will compare CXCR3+CCR6+CD4+ T cells in TB-IRIS versus non-TB-IRIS patients to determine their anti-MTb function. Findings from these experiments will provide critical insights into how TB co-infection in HIV+ patients affects phenotypic and epigenetic features of the immune system prior to and following ART-mediated immune reconstitution, and they will elucidate the long-term consequences of TB-IRIS on functional MTb-specific T cell responses that were associated with successful ART-mediated immune reconstitution and TB cure.