Host factors, inflammation, and HIV associated TB

宿主因素、炎症和 HIV 相关结核病

基本信息

批准号：
9114703
负责人：
ANNE GOLDFELD
金额：
$ 81.29万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9114703
关键词：
Acquired Immunodeficiency Syndrome Activities of Daily Living Affect Aftercare Antigens Antitubercular Agents Archives Biological Markers CCR5 gene CCR6 gene CD4 Positive T Lymphocytes CD8B1 gene CXCR3 gene Cause of Death Cell Count Cells Characteristics Clinical Containment Data Disease Environment Epigenetic Process Epitopes Frequencies Future Growth HIV HIV-1 Health Immune Immune response Immune system Individual Infection Inflammation Integration Host Factors Interleukin-5 Lead Link Long-Term Effects Lung Lung diseases Mediating Memory Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Outcome Patients Peripheral Peripheral Blood Mononuclear Cell Persons Phase Play RNA Randomized Clinical Trials Randomized Controlled Trials Recording of previous events Relapse Relative (related person)Risk Role SELL gene Sampling Staging Syndrome T cell response T-Cell Activation T-Cell Development T-Lymphocyte Testing Th1 Cells Time Treatment Protocols Treatment outcome Tropism Tuberculosis Viral Virus abstracting antiretroviral therapy base co-infection cohort epigenetic marker experience immunosuppressed improved in vitro Assay insight memory CD4 T lymphocyte monocyte mortality novel peripheral blood prevent reconstitution research study response terminally differentiated effector memory (TEM) T cells tuberculosis treatment vaccine development

项目摘要

DESCRIPTION (provided by applicant): Although infection with Mycobacterium tuberculosis (MTb) is the largest cause of death in AIDS, and it is the major cause of HIV-associated pulmonary disease globally, little is known about how TB co-infection impacts long term immune reconstitution or the HIV-1 reservoir. The Cambodian Early vs. Late Introduction of Anti- retrovirals (ART) (CAMELIA) randomized clinical trial showed that early initiation of ART (2 weeks after TB therapy initiation versus late ART at 8 weeks), resulted in a significant (34%) decrease in mortality in TB+/HIV+ patients with a CD4+ T cell count <200 cells/mm, a survival benefit that persisted for at least 3 years. Our preliminary data examining T cell responses in TB+/HIV+ individuals from the CAMELIA randomized clinical trial in a nested substudy, demonstrated that TB and TB-associated immune reconstitution syndrome (TB-IRIS) results in profound changes in the T cell compartment for at least 8 months after treatment initiation. For example, TB co-infection and TB-IRIS is associated with massive T cell activation including elevated CCR5+ T cells and results in significant impact on the proportions of central memory (TCM) (CD62L+CD45RA-) CD4+T cells, the major peripheral HIV reservoir component and effector memory. In patients who experienced TB- IRIS, we observed a reciprocal expansion of T effector (TEM) (CD62L-CD45RA-) CD4+T cells, which are associated with control TB. Furthermore, TB-IRIS patients had elevated CXCR3+CCR6+CD4+ T cells, which are thought to mediate a large portion of CD4+ anti-TB responses, and these CXCR3+CCR6+CD4+ T cells remained significantly elevated for at least 8 months after the initiation of ART. Based on our preliminary data, we hypothesize that the distinct cellular responses we observed in TB-IRIS may represent important protective responses to TB. We hypothesize that evaluating these responses in former CAMELIA patients cured of TB and on stable ART in a TB endemic environment will lead to identification of novel antigens important for protective responses and future vaccine development. Host biomarkers of TB infection, TB-IRIS and TB/HIV co-infection and linked clinical outcomes are lacking. Using RNA microarrays, we will determine signatures associated with TB co-infection, TB-IRIS, and antigen specific TB responsiveness. We hypothesize that this analysis in this extremely well-characterized patient cohort will provide robust and novel biomarkers of TB co- infection, containment of TB disease, and protective responses associated with in vitro assays. Finally, using archived PBMC, from TB+/ HIV+ patients from CAMELIA or TB-/HIV+ patients with similar baseline characteristics who began ART at the same time, we will test the hypothesis that TB co-infection and TB-IRIS modulate HIV reservoir tropism after ART initiation the months after ART initiation and years later and potentially also influence reservoir size. Findings from these experiments will be of great value for improving both treatment of TB/HIV co-infection and our general understanding of the host immune response to TB/HIV as well as providing the first evidence indicating that TB co-infection can affect the composition of the HIV reservoir.

描述（由申请人提供）：尽管结核分枝杆菌（MTB）的感染是艾滋病中最大的死亡原因，它是全球与HIV相关的肺部疾病的主要原因，但对于TB共同感染如何影响长期的免疫侵犯或HIV-1水库，对TB共同感染如何影响。柬埔寨早期与晚期引入抗逆转录病毒（ART）（Camelia）随机临床试验表明，早期开始艺术（结核病治疗倡议后2周周），导致CD4+ T细胞计数<200细胞/mm的TB+/HIV+患者的死亡率显着降低（34％），这是一种生存益处，至少持续了3年。我们的初步数据研究了来自嵌套的Camelia随机临床试验中TB+/HIV+个体中T细胞反应，这表明TB和TB相关的免疫重建综合征（TB-IRIS）在治疗后至少8个月会导致T细胞隔室的深刻变化。例如，TB共感染和TB-IRI与大量T细胞激活有关，包括CCR5+T细胞升高，并对中央记忆（TCM）（CD62L+CD45RA-）CD4+T细胞产生重大影响，这是主要的外围HIV HIV HIV HIV储层组件和效应记忆。在经历了TB-IRIS的患者中，我们观察到与对照结核有关的T效应子（TEM）（TEM）（CD62L-CD45RA-）CD4+T细胞的相互扩展。此外，TB-IRIS患者的CXCR3+CCR6+CD4+T细胞升高，被认为可以介导很大一部分CD4+抗TB反应，并且这些CXCR3+CCR6+CD4+T细胞在艺术创业后至少8个月保持了至少8个月的显着升高。根据我们的初步数据，我们假设在TB-IRI中观察到的不同细胞反应可能代表对TB的重要保护反应。我们假设评估TB内疗和稳定ART的前骆驼患者中评估这些反应将导致对受保护反应和未来疫苗发育重要的新型抗原的鉴定。缺乏结核病感染，TB-IRI和TB/HIV共同感染的宿主生物标志物以及连接的临床结果。使用RNA微阵列，我们将确定与TB共感染，TB-IRI和抗原特异性结核病响应性相关的特征。我们假设这种分析在这种非常良好的患者队列中，将提供结核病共同感染，结核病抑制以及与体外测定相关的受保护反应的强大而新颖的生物标志物。最后，使用档案中的PBMC，来自Camelia或TB-/ HIV+具有相似基线特征的患者的TB+/ HIV+患者同时开始艺术的患者，我们将检验以下假设：TB共同感染和TB-IRIS调节了Artiative of Atiative of Atiative and Iniatiative and Intiriative and Intirative and Mepitive and tositive and Posity and潜入潜力和潜在的Artientally和Reserveir size size size。这些实验的发现对于改善TB/HIV共同感染的治疗以及我们对宿主对TB/HIV的免疫反应的一般理解以及提供第一个证据表明TB共同感染会影响HIV储量的组成。