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.
这项工作的前提是我们小组和其他人的观察:a)在治疗之前

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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