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

虽然结核分枝杆菌感染是肺部疾病和死亡的最大原因 在全球艾滋病患者中，关于结核病合并感染如何影响长期抗逆转录病毒（ART）的研究知之甚少， 介导的免疫重建。柬埔寨抗逆转录病毒药物的早期与晚期引入（CAMELIA） 随机临床试验显示，在结核病治疗开始后2周早期开始抗逆转录病毒治疗与晚期抗逆转录病毒治疗相比， 在严重免疫功能低下的TB+/HIV+患者中（中位CD 4 =24/mm 3）， 导致死亡率显著降低（34%），这一生存益处持续至少3年， 时间干预。在CAMELIA试验的一项科学子研究中，我们发现， 在这些高度免疫抑制的TB+/HIV+患者中，活动性TB疾病导致ART前 几种促炎细胞因子的水平和更高的ART前活化的CD 4+和CD 8 + T细胞频率 细胞，以及显著降低ART前CD 28 + CD 8+和ICOS+ CD 4 + T细胞的频率， 结核病-/艾滋病毒+患者。此外，T细胞亚群频率的这些差异持续至少8个月， 治疗开始后和TB治愈后2个月。此外，我们已经证明，结核病相关的 免疫重建综合征（TB-IRIS），在早期CAMELIA中发生率高2.6倍 治疗组中，导致T细胞区室的深刻变化。例如，TB-IRIS患者 显示出（CD 62 L-CD 45 RA-）效应记忆CD 4 +T细胞的显著ART后扩增和（CD 62 L-CD 45 RA-）效应记忆CD 4 +T细胞的减少。 在（CD 62 L + CD 45 RA-）中枢记忆性CD 4 +T细胞中，与非TB-IRIS患者相比。我们还发现 Th 1样CD 4 + T细胞亚群是CXCR 3 + CCR 6+，被认为介导了大部分抗TB 在TB-IRIS患者中，ART前的反应频率显著升高， 这些细胞在治疗开始后至少8个月保持升高。根据初步数据，我们 假设结核病合并感染加剧了艾滋病毒诱导的免疫系统过早老化，导致 长期后果和不良的回忆反应。在目标1中，我们将研究免疫衰老， 来自TB+/HIV+ CAMELIA和TB-/HIV+和TB+的治疗前存档样本中的甲基化组特征 /艾滋病毒-患者，以及在结核病治疗和抗逆转录病毒治疗后>5年的同一患者的新鲜分离样本中 入会仪式我们进一步假设，在TB+/HIV+组中，经历TB-的患者亚组 IRIS具有上级抗MTb免疫力，一旦开始ART，该免疫力被放大。在目标2中， 比较TB-IRIS与非TB-IRIS患者中的CXCR 3 + CCR 6 + CD 4 + T细胞，以确定其抗MTb 功能这些实验的结果将为HIV+患者中的结核合并感染如何提供重要的见解 在ART介导的免疫之前和之后影响免疫系统的表型和表观遗传特征 重建，他们将阐明TB-IRIS对功能性MTb特异性T细胞的长期影响。 与成功的ART介导的免疫重建和TB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.