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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：
OLIVER CHUKWUJEKWU EZECHI
金额：
$ 68.21万
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/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

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