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:
    10326900
  • 负责人:
  • 金额:
    $ 68.21万
  • 依托单位:
  • 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

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)在治疗前, 艾滋病毒会使艾滋病毒携带者骨质流失; B)抗逆转录病毒疗法会使 急性骨丢失,但这种损失的程度因人而异,从轻度到中度, 严重,并且发生在ART开始后的定义窗口(约6个月)内; c)随着PWH年龄的增长, HIV/ART-骨丢失与自然老化骨丢失相结合。我们认为急性抗逆转录病毒疗法诱导的骨 损失是由于免疫重建,并由响应微生物抗原的T细胞活化驱动, 艾滋病病毒引起的肠道损伤和微生物移位加剧了这种情况。重要的是,由于这种急性骨丢失是 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的骨质流失。 值得注意的是,驱动炎症的免疫激活是抗原依赖性的。T细胞通过大量的 独特的T细胞受体(TCR)库。虽然ART导致部分T细胞恢复,但由于成年胸腺 当T细胞萎缩时,T细胞主要通过预先存在的记忆T细胞的稳态扩增而不是死亡来重新增殖。 novo.因此,ART可能会扩增在HIV中存活的T细胞克隆,因为它们对持续性HIV感染具有高反应性。 自身抗原和外来抗原。由于HIV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Th17 T细胞扩增和易位到骨骼 在骨髓中,它们分泌破骨细胞生成效应因子RANKL,以及IL-17 A和TNF α,两者都是有效的𝛼 RANKL的诱导剂。此外,LPS是肠道通透性的标志物,是促进骨形成的炎症产物, 通过破骨细胞生成性细胞因子(包括IL-1、IL-6、TNF α)和/或通过Toll样细胞因子直接破骨细胞作用导致的损失。𝛼 受体包括TLR4。因此,HIV诱导的肠道损伤可能会增加炎性骨丢失。 因此,肠道免疫相互作用可以解释免疫重建骨丢失中注意到的受试者间差异 (IRBL),因为PWH之间的肠道泄漏和微生物组特征差异很大。 因此,在本申请中,我们提出了一个机制的动物研究,以建立抗原呈递的作用 和微生物群在IRBL小鼠模型中的作用(Aim 1),以及一项补充的人类临床研究,以验证其作用 PWH中ART诱导的IRBL中的微生物群、Th17细胞和肠道通透性(目的2)。完成后,我们 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 协助识别有严重IRBL风险的威尔斯亲王医院,并提供强而有力的理据, 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。

项目成果

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OLIVER CHUKWUJEKWU EZECHI其他文献

OLIVER CHUKWUJEKWU EZECHI的其他文献

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{{ truncateString('OLIVER CHUKWUJEKWU EZECHI', 18)}}的其他基金

Sustaining Innovative Tools to Expand Youth-Friendly HIV Self-Testing (S-ITEST)
维持创新工具以扩大青少年友好型艾滋病毒自我检测 (S-ITEST)
  • 批准号:
    10933892
  • 财政年份:
    2024
  • 资助金额:
    $ 68.21万
  • 项目类别:
Innovative Tools to Expand Music-Inspired Strategies for Blood Pressure and Stroke Prevention (I-TEST BP/Stroke)
扩展受音乐启发的血压和中风预防策略的创新工具(I-TEST BP/中风)
  • 批准号:
    10937709
  • 财政年份:
    2023
  • 资助金额:
    $ 68.21万
  • 项目类别:
US-Nigerian Cancer Control Center for Research on Implementation Science and Equity (C3-RISE)
美国-尼日利亚癌症控制实施科学与公平研究中心 (C3-RISE)
  • 批准号:
    10738439
  • 财政年份:
    2023
  • 资助金额:
    $ 68.21万
  • 项目类别:
Actions for Collaborative Community Engaged Strategies for HPV (ACCESS HPV)
HPV 社区参与协作策略行动 (ACCESS HPV)
  • 批准号:
    10708926
  • 财政年份:
    2022
  • 资助金额:
    $ 68.21万
  • 项目类别:
Actions for Collaborative Community Engaged Strategies for HPV (ACCESS HPV)
HPV 社区参与协作策略行动 (ACCESS HPV)
  • 批准号:
    10587502
  • 财政年份:
    2022
  • 资助金额:
    $ 68.21万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 68.21万
  • 项目类别:
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:
    10701767
  • 财政年份:
    2021
  • 资助金额:
    $ 68.21万
  • 项目类别:
Integration of Hypertension Management into HIV Care in Nigeria: A Task Strengthening Strategy
尼日利亚将高血压管理纳入艾滋病毒护理:任务强化策略
  • 批准号:
    10337310
  • 财政年份:
    2020
  • 资助金额:
    $ 68.21万
  • 项目类别:
Integration of Hypertension Management into HIV Care in Nigeria: A Task Strengthening Strategy
尼日利亚将高血压管理纳入艾滋病毒护理:任务强化策略
  • 批准号:
    10365181
  • 财政年份:
    2020
  • 资助金额:
    $ 68.21万
  • 项目类别:
Integration of Hypertension Management into HIV Care in Nigeria: A Task Strengthening Strategy
尼日利亚将高血压管理纳入艾滋病毒护理:任务强化策略
  • 批准号:
    9926582
  • 财政年份:
    2020
  • 资助金额:
    $ 68.21万
  • 项目类别:

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