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

• 批准号: 10491843
• 负责人: OLIVER CHUKWUJEKWU EZECHI
• 金额: $ 66.15万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/10491843
• 关键词: Acute; Adult; 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; Data; Disease; Equilibrium; Estrogens; Feces; Fracture; Future; Grant; HIV; HIV Infections; HIV antiretroviral; Human; Immune; Immune system; Immunologic Markers; Inflammation; Inflammatory; Integrase; Interleukin-1; Interleukin-17; Interleukin-6; Intervention; Intestinal permeability; Leaky Gut; Ligands; Memory; Metagenomics; Modernization; Mus; NF-kappa B; Natural regeneration; Osteoblasts; Osteoclasts; Pathologic; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Physiological; Play; Prevention strategy; Probiotics; Process; Production; Recovery; Regimen; 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; TRANCE protein; Tenofovir; Testing; Therapeutic; Thymus Gland; Time; Toll-like receptors; Tumor necrosis factor receptor 11b; Work; antiretroviral therapy; base; bone; bone loss; bone mass; bone turnover; cytokine; experience; gut microbiome; 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

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.

这项工作的前提是我们小组和其他人的观察：a)在治疗之前 HIV病毒导致艾滋病毒携带者骨质丢失(PWH)；b)抗逆转录病毒疗法(ART)导致额外的 急性骨丢失，但这种丢失的程度因人而异，从轻微到 深刻的，并发生在ART开始后的限定窗口(~6个月)内；c)随着PWH年龄的增长， 人类免疫缺陷病毒/抗逆转录病毒抗逆转录病毒治疗--骨丢失是由自然衰老引起的骨丢失。我们认为急性ART诱导的骨 损失是由于免疫重建，并由T细胞对微生物抗原和 艾滋病毒引起的肠道损伤和微生物移位加剧了这一现象。重要的是，由于这种急性骨质流失 在免疫激活的推动下，即使是较新的抗逆转录病毒药物也会导致易感患者严重的骨丢失。 值得注意的是，免疫激活驱动炎症是抗原依赖的。T细胞通过大量的 独特的T细胞受体(TCR)谱系。尽管ART可以导致T细胞的部分恢复，因为成人胸腺 是萎缩性的，T细胞的重新填充主要是通过体内平衡扩张原有的记忆T细胞，而不是死亡 诺沃。因此，ART可能会扩大在HIV病毒中幸存下来的T细胞克隆，因为它们对持久性具有高反应性 自身抗原和外源抗原。艾滋病毒引起的肠道损伤导致的微生物移位可能会加剧炎症。 肠道免疫相互作用的另一个有趣特征是Th17T细胞的扩张和移位到骨骼 在骨髓中，它们分泌破骨细胞因子RANKL，以及IL-17A和肿瘤坏死因子𝛼，两者都是有效的 RANKL的诱导者。此外，内毒素，肠道通透性的标志，是一种促进骨骼的炎症产物 通过破骨细胞因子丢失，包括IL-1、IL-6、肿瘤坏死因子𝛼，和/或通过Toll样的直接破骨细胞作用 受体包括TLR4。因此，HIV引起的肠道损伤很可能会加剧炎症性骨丢失。 因此，肠道免疫相互作用可能解释了免疫重建中骨丢失的受试者之间的差异。 (IRBL)AS肠道渗漏和微生物组图谱在不同PWH之间差异很大。 因此，在这一应用中，我们建议进行一项机械性的动物研究，以确定抗原提呈的作用。 和微生物群在IRBL小鼠模型中的作用(Aim 1)，以及一项免费的人类临床研究来验证这一作用 ART诱导的PWH中IRBL的微生物区系、Th17细胞和肠道通透性的研究(目标2)。完成后，我们将 期望在肠道渗漏、肠道微生物区系、免疫激活和 IRBL，并证明这些关系因人而异。这项工作的发现将 为确定威尔斯亲王医院面临严重IRBL风险的持续努力做出贡献，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。