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

• 批准号: 9303303
• 负责人: ANNE GOLDFELD
• 金额: $ 21.84万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-24 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303303
• 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; CD8-Positive T-Lymphocytes; CD8B1 gene; CDKN2A gene; CXCR3 gene; Cambodia; Cambodian; Cause of Death; Cell Compartmentation; Cell Count; Cell Differentiation process; Cells; Cessation of life; Clinical; Clone Cells; DNA Methylation; Data; Differentiation Antigens; Disease; Environment; Epigenetic Process; Exhibits; Frequencies; Future; Growth; HIV; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunologics; Immunophenotyping; Immunosuppression; Individual; Infection; Inflammatory; Intervention; Lead; 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 response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Transcript; Tuberculosis; adaptive immune response; adaptive immunity; aged; antiretroviral therapy; arm; base; clinical biomarkers; co-infection; cohort; cytokine; design; experience; experimental study; immunosuppressed; insight; memory CD4 T lymphocyte; methylome; mortality; novel therapeutic intervention; novel therapeutics; patient subsets; peripheral blood; phenotypic biomarker; premature; prophylactic; reconstitution; response; senescence; terminally differentiated effector memory (TEM) T cells; trend; tuberculosis immunity; tuberculosis treatment

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 在全球艾滋病毒患者中，人们对结核病合并感染如何影响长期抗逆转录病毒 (ART) 的影响知之甚少。 柬埔寨早期与晚期引入抗逆转录病毒药物（CAMELIA） 随机临床试验表明，与较晚开始结核病治疗后 2 周早期开始 ART 相比， 严重免疫功能低下的 TB+/HIV+ 患者在第 8 周开始 ART（中位 CD4=24/mm3）， 导致死亡率显着下降（34%）——生存获益在术后至少持续 3 年 在 CAMELIA 试验中的一项科学子研究中，我们发现了这一点。 这些高度免疫抑制的 TB+/HIV+ 患者的活动性结核病导致 ART 前显着增加 多种促炎细胞因子的水平以及活化 CD4+ 和 CD8+ T 的 ART 前频率更高 细胞，并且与相比，CD28+CD8+和ICOS+CD4+T细胞的ART前频率显着降低 此外，TB-/HIV+患者的T细胞亚群频率差异持续了至少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，结核病相关。 免疫重建综合征 (TB-IRIS)，其发生频率在早期 CAMELIA 中增加 2.6 倍 治疗组会导致 T 细胞区室发生深刻变化，例如 TB-IRIS 患者。 ART 后 (CD62L-CD45RA-) 效应记忆 CD4+T 细胞显着扩增，并且减少 我们还发现，与非 TB-IRIS 患者相比，(CD62L+CD45RA-) 中央记忆 CD4+T 细胞中。 Th1 样 CD4+ T 细胞亚群是 CXCR3+CCR6+，被认为介导大部分抗结核病 TB-IRIS 患者在 ART 前出现反应的频率显着升高，并且 根据我们的初步数据，这些细胞在治疗开始后至少 8 个月内保持升高状态。 结核病合并感染加剧了艾滋病毒引起的免疫系统过早衰老，导致 在目标 1 中，我们将研究免疫衰老和不良记忆反应。 TB+/HIV+ CAMELIA 和 TB-/HIV+ 和 TB+ 治疗前存档样本中的甲基组特征 /HIV- 患者，以及来自结核病治疗和 ART 后 >5 年的同一患者的新鲜分离样本 我们进一步研究了 TB+/HIV+ 组中经历过 TB- 的患者子集。 IRIS 具有卓越的抗 MTb 免疫力，一旦开始 ART，这种免疫力就会增强。在目标 2 中，我们将增强这种免疫力。 比较 TB-IRIS 与非 TB-IRIS 患者中的 CXCR3+CCR6+CD4+ T 细胞，以确定其抗 MTb 这些实验的结果将为了解艾滋病毒+患者中的结核病合并感染提供重要见解。 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 介导的免疫重建和结核病治愈相关的反应。