Predictors of Antiretroviral Immunereconstitution Bone Loss - the Gut and the Microbiome

抗逆转录病毒免疫重建骨丢失的预测因素 - 肠道和微生物组

基本信息

批准号：
10701767
负责人：
OLIVER CHUKWUJEKWU EZECHI
金额：
$ 66.82万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-21 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10701767
关键词：
Ablation Acute Adult Age Aging Animals Anti-Retroviral Agents Antibiotics Antigen Presentation Antigens Atrophic Automobile Driving B-Lymphocytes Bacteria Basic Science Bone Density Bone Diseases Bone Marrow Bone Resorption Cells Clinical Research Clone Cells Complication Cytoprotection Data Disease Equilibrium Estrogen deficiency Feces Fracture Future Grant HIV HIV Infections Human Hyperparathyroidism IL17 gene Immune Immune system Immunologic Deficiency Syndromes Immunologic Markers Inflammation Inflammatory Integrase Interleukin-1 Interleukin-6 Intervention Intestinal permeability Leaky Gut Ligands Metagenomics Modernization Mus NF-kappa B Natural regeneration Osteoblasts Osteoclasts Pathologic Pathway interactions Patients Persons Pharmaceutical Preparations Physiological Predisposition Prevention strategy Probiotics Process Production Recovery Regimen Rejuvenation Reporting Risk Role Serum Serum Markers Severities Shotgun Sequencing Skeletal system Skeleton T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte TLR4 gene Tenofovir Testing Therapeutic Thymus Gland Time Toll-like receptors Tumor necrosis factor receptor 11b Virus Work antiretroviral therapy biomarker identification bone bone loss bone mass bone turnover cytokine experience gut microbiota immune activation immune reconstitution indexing inflammatory bone loss inhibitor microbial microbiome microbiota microorganism antigen mouse model osteoclastogenesis predictive marker preservation prevent preventive intervention receptor response risk stratification

项目摘要

The premise of this work is anchored on the observation by our group and others that: a) prior to treatment the HIV virus inflicts bone loss in persons living with HIV (PWH); b) Antiretroviral therapy (ART) inflicts additional acute bone loss, but the magnitude of this loss varies widely from person to person, ranging from mild to profound, and occurs within a defined window (~6 months) following ART initiation and; c) As PWH age, HIV/ART-bone loss is compounded by natural aging bone loss. We contend that the acute ART-induced bone loss is due to immune reconstitution and is driven by T cell activation in response to microbial antigens and intensified by HIV-induced gut damage and microbial translocation. Importantly, as this acute bone loss is driven by immune activation, even newer ART drugs cause severe bone loss in susceptible patients. Of note, immune activation driving inflammation is antigen-dependent. T cells recognize antigens via a vast repertoire of unique T cell receptors (TCRs). Although ART leads to partial T cell recovery, as the adult thymus is atrophic, T cells repopulate mainly via homeostatic expansion of preexisting memory T cells rather than de novo. ART, thus, likely expands T cell clones that have survived HIV as they are hyper-reactive to persistent self- and foreign-antigens. Microbial translocation due to HIV-induced gut damage may intensify inflammation. Another interesting feature of the gut-immune interaction is Th17 T cell expansion and translocation to the bone marrow where they secrete the osteoclastogenic effector RANKL, as well as IL-17A and TNF𝛼, both potent inducers of RANKL. Further, LPS, a marker of gut permeability, is an inflammatory product that promotes bone loss through osteoclastogenic cytokines, including IL-1, IL-6, TNF𝛼, and/or direct osteoclast effects via Toll-like receptors including TLR4. It is therefore likely that HIV-induced gut damages enhance inflammatory bone loss. Gut-immune interaction may thus explain the inter-subject variability noted in immune reconstitution bone loss (IRBL) as gut leakiness and microbiome profile vary widely among PWH. In this application, we therefore propose a mechanistic animal study to establish a role for antigen presentation and microbiota in a mice model of IRBL (Aim 1), and a complimentary human clinical study to validate the role of microbiota, Th17 cells, and gut permeability in ART-induced IRBL in PWH (Aim 2). Upon completion, we expect to establish strong relationships between gut leakiness, intestinal microbiota, immune activation and IRBL and demonstrate that these relationships vary widely from person to person. Findings from this work will contribute to ongoing efforts aimed at identifying PWH at risk for severe IRBL and provide strong rationale for exploring targeted preventive interventions including probiotics and/or CD4+ Th17/IL-17A inhibitors.

这项工作的前提是基于我们小组和其他人的观察：a) 在治疗之前 HIV 病毒导致 HIV 感染者 (PWH) 骨质流失 b) 抗逆转录病毒治疗 (ART) 造成额外的骨质流失；急性骨质流失，但这种流失的程度因人而异，从轻微到严重不等。范围广泛，并且发生在 ART 开始后的规定窗口内（约 6 个月）；c) 随着 PWH 年龄的增加， HIV/ART 引起的骨质流失与自然衰老骨质流失相结合，我们认为急性 ART 引起的骨质流失。损失是由于免疫重建造成的，并且是由响应微生物抗原和 T 细胞激活所驱动的。重要的是，这种急性骨质流失会因艾滋病毒引起的肠道损伤和微生物移位而加剧。在免疫激活的驱动下，即使是较新的 ART 药物也会导致易感患者严重骨质流失。值得注意的是，驱动炎症的免疫激活是抗原依赖性的。尽管 ART 会导致部分 T 细胞恢复，就像成人胸腺一样。萎缩时，T 细胞主要通过先前存在的记忆 T 细胞的稳态扩张而不是去因此，ART 可能会扩大 HIV 存活下来的 T 细胞克隆，因为它们对持续性反应过度。 HIV 引起的肠道损伤导致的自身和外来抗原的微生物易位可能会加剧炎症。肠道-免疫相互作用的另一个有趣特征是 Th17 T 细胞扩增和易位至骨骼它们在骨髓中分泌破骨细胞效应因子 RANKL，以及 IL-17A 和 TNF𝛼，两者均有效此外，LPS（肠道通透性标志物）是一种促进骨生长的炎症产物。通过破骨细胞因子（包括 IL-1、IL-6、TNF𝛼）和/或通过 Toll 样直接破骨细胞作用而损失因此，HIV 引起的肠道损伤可能会加剧炎症性骨质流失。因此，肠道-免疫相互作用可以解释免疫重建骨质流失中的受试者间变异性（IRBL），因为感染者之间的肠道渗漏和微生物组特征差异很大。因此，在本申请中，我们提出了一项机械动物研究来确定抗原呈递的作用 IRBL 小鼠模型中的微生物和微生物群（目标 1），以及验证其作用的免费人体临床研究 ART 诱导的 IRBL 中的微生物群、Th17 细胞和肠道通透性的变化（目标 2）。期望在肠道渗漏、肠道微生物群、免疫激活和 IRBL 并证明这些关系因人而异。这项工作的结果将表明。为持续努力识别有严重 IRBL 风险的 PWH 做出贡献，并为探索有针对性的预防干预措施，包括益生菌和/或 CD4+ Th17/IL-17A 抑制剂。