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

高度免疫抑制的艾滋病毒感染者和未感染者对结核病的免疫力

基本信息

批准号：
9205082
负责人：
ANNE GOLDFELD
金额：
$ 26.97万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-24 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9205082
关键词：
Acquired Immunodeficiency Syndrome Address Affect Aftercare Aging Anti-Retroviral Agents Antitubercular Agents Archives Biological Markers Blood Cells CCR6 gene CD28 gene CD4 Positive T Lymphocytes CD8B1 gene CDKN2A gene CXCR3 gene Cambodia Cambodian Cause of Death Cell Count Cells Cessation of life Clinical DNA Methylation Data Differentiation Antigens Disease Environment Epigenetic Process Exhibits Frequencies Future Growth HIV Immune Immune response Immune system Immunity Immunocompromised Host Immunophenotyping Immunosuppression Individual Infection Inflammatory Intervention Lead Life Lung diseases Measures Mediating Mediator of activation protein Memory Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Patients Phenotype Premature aging syndrome Proliferating Pulmonary Tuberculosis Randomized Clinical Trials Recruitment Activity SELL gene Sampling Serum Subgroup Syndrome T cell differentiation T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Testing Time Transcript Tuberculosis adaptive immunity aged antiretroviral therapy arm base clinical biomarkers co-infection cohort cytokine design experience immunosuppressed insight memory CD4 T lymphocyte methylome mortality novel therapeutic intervention novel therapeutics patient subsets peripheral blood phenotypic biomarker premature prophylactic reconstitution research study response senescence terminally differentiated effector memory (TEM) T cells trend tuberculosis immunity tuberculosis treatment

项目摘要

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.

尽管结核分枝杆菌（MTB）感染是肺部疾病和死亡的最大原因在全球HIV患者中，关于结核病感染如何影响长期抗逆转录病毒（ART） - 介导的免疫机构。柬埔寨早期与晚期引入抗逆转录病毒（Camelia）随机临床试验表明，结核病治疗开始后2周，早期开始艺术在严重免疫功能低下的TB+/HIV+患者（中位CD4 = 24/mm3）中，在8周时开始ART 导致死亡率的显着降低（34％） - 这种生存益处至少在3年后持续定时干预。在嵌套在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+患者中的活性结核病导致了明显更大的前艺术激活的CD4+和CD8+ T的几种促炎细胞因子的水平和较大的前ART频率细胞，并且与CD28+ CD8+和ICOS+ CD4+ T细胞的图前频率显着降低 TB-/HIV+患者。此外，T细胞子集频率的这些差异至少持续了8个月治疗倡议后，结核病治疗后2个月。此外，我们已经证明了与TB相关的免疫重建综合征（TB-IRI），在凉茶早期发生的频率更高2.6倍治疗部门，导致T细胞室的深刻变化。例如，TB-IRIS患者暴露了（CD62L-CD45RA-）效应器记忆CD4+T细胞的显着后膨胀和降低与非TB-IRIS患者相比，在（CD62L+CD45RA-）中央记忆CD4+T细胞中。我们也发现 cxcr3+ ccr6+的Th1状CD4+ T细胞子集，并被认为介导了很大一部分抗TB 在TB-IRIS患者中，在频率明显升高的情况下存在反应，频率是这些细胞在治疗发作后至少升高8个月。根据我们的初步数据，我们假设结核病的共感染加剧了艾滋病毒诱导的免疫系统的过早衰老，导致长期后果和召回不良的反应。在AIM 1中，我们将调查免疫感和来自TB+/HIV+ Camelia和TB-/HIV+和TB+的预处理预处理样品中的甲基化学特征 /HIV-患者，以及在结核病治疗和ART后5年的同一患者的新鲜隔离样品中引发。我们进一步假设，在TB+/HIV+组中，经历了TB-的患者的子集艾里斯（Iris）具有优质的抗MTB免疫史地性，一旦开始ART，它就会放大。在目标2中，我们将比较TB-IRI与非TB-IRIS患者的CXCR3+CCR6+CCR6+CD4+T细胞以确定其抗MTB 功能。这些实验的发现将提供有关HIV+患者TB共感染的关键见解在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组，他们将阐明TB-IRIS对功能MTB特异性T细胞的长期后果与成功的ART介导的免疫宪法和结核病治疗相关的反应。