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: 10326900
• 负责人: OLIVER CHUKWUJEKWU EZECHI
• 金额: $ 68.21万
• 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/10326900
• 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/antagonist; 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的小组和其他人的观察结果：a）在治疗之前 艾滋病毒病毒会导致艾滋病毒感染者（PWH）造成骨质流失； b）抗逆转录病毒疗法（ART）会造成其他 急性骨质流失，但这种损失的幅度范围从人到人的范围很广，从轻度到 深刻，并且发生在明定的窗口（约6个月）之内，并在艺术计划之后； c）作为PWH年龄， 艾滋病毒/艺术骨损失因自然衰老的骨质流失而使艾滋病毒丧失更加复杂。我们认为急性艺术引起的骨头 损失是由于免疫宪法造成的，是由T细胞激活驱动的，响应微生物抗原和 通过HIV引起的肠道损伤和微生物易位加强。重要的是，由于这种急性骨质流失是 在免疫激活的驱动下，甚至更新的ART药物在易感患者中导致严重的骨质流失。 值得注意的是，免疫激活驱动炎症是抗原依赖性的。 T细胞通过宽阔的抗原识别抗原 尽管艺术导致部分T细胞恢复，但由于成年百里香 是萎缩性的，T细胞主要通过先前存在的记忆T细胞而不是DE来重新填充 Novo。因此，ART可能会扩大在HIV中幸存下来的T细胞克隆，因为它们具有持久性的反应性 自我抗原。由于艾滋病毒引起的肠道损伤引起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细胞膨胀和转移到骨头 他们分泌破骨细胞生成效应器RankL以及IL-17A和TNF𝛼的骨髓，都有效 Rankl的诱导者。此外，LPS是肠道通透性的标志物，是一种促进骨骼的炎症产物 通过破骨细胞因子的损失，包括IL-1，IL-6，TNF𝛼和/或直接的破骨细胞效应。 包括TLR4在内的受体。因此，艾滋病毒引起的肠道损害可能会增强炎症性骨质流失。 因此，肠道免疫相互作用可以解释免疫宪法骨质流失中指出的受试者间变异性 （IRBL）作为肠泄漏和微生物组轮廓在PWH之间差异很大。 因此，在此应用中，我们提出了一项机械动物研究，以确立抗原表现的作用 和IRBL小鼠模型中的微生物群（AIM 1）和免费的人类临床研究以验证角色 在ART诱导的PWH中，微生物群，Th17细胞和肠道渗透性（AIM 2）。完成后，我们 期望在肠道泄漏，肠道菌群，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 为旨在确定有可能发生严重IRBL风险的PWH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。