Impact of HIV and antiretroviral initiation on skeletal biology

HIV 和抗逆转录病毒治疗对骨骼生物学的影响

• 批准号: 10657701
• 负责人: Rosa Maria Affonso Moyses
• 金额: $ 18.79万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657701
• 关键词: Adult; Aftercare; Aging; Anti-Retroviral Agents; Area; Biological Assay; Biology; Biopsy; Biopsy Specimen; Bone Density; Bone Marrow; Bone structure; Brazil; Cellularity; Child; Collaborations; Data; Defect; Development; Disease; Disease Progression; Dual-Energy X-Ray Absorptiometry; Elderly; Enrollment; Exposure to; Finite Element Analysis; Fracture; Fumarates; Functional disorder; Genes; Goals; HIV; HIV Infections; HIV/AIDS; Hardness; Image; Inflammation; Institution; Integrase; Interdisciplinary Study; Lamivudine; Longitudinal Studies; Measures; Mechanics; Medical center; Minerals; Molecular; Musculoskeletal; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Osteoblasts; Osteogenesis; Osteoid; Osteoporosis; Participant; Pathogenesis; Pathway interactions; Peripheral; Persons; Physiologic calcification; Population; Property; Protease Inhibitor; Protocols documentation; Recovery; Regimen; Research; Research Personnel; Research Technics; Resolution; Safety; Specimen; Spectrum Analysis; Tenofovir; Time; Tissues; Universities; Woman; X-Ray Computed Tomography; Yin; abacavir; antiretroviral therapy; bone; bone cell; bone imaging; bone loss; bone mass; bone metabolism; bone quality; bone strength; cohort; design; efavirenz; improved; inhibitor; interest; laboratory experience; low and middle-income countries; mechanical properties; men; mineralization; nanoindentation; perinatal HIV; prevent; repository; senescence; skeletal; tibia; training opportunity; transcriptomics; young man

ABSTRACT Osteoporosis and fractures are known complications of HIV and antiretroviral therapy (ART). Bone mineral density (BMD) decreases 2-4% within the first year after ART initiation and is worse with exposure to specific ART such as tenofovir disoproxil fumarate (TDF). The mechanisms of HIV and ART associated bone loss are still uncertain because tissue-level data are lacking. Through a collaboration between investigators at Columbia University and University of São Paulo with complementary expertise in HIV and bone research, we were able to perform the first comprehensive longitudinal bone biopsy study in ART-naïve young men before and 12 months after initiation of TDF/lamivudine/efavirenz. We found evidence of bone formation and mineralization abnormalities before ART. After ART, there was an increase in bone cellularity, but a persistence in bone mineralization defects. Our goal is to enroll adult ART-naïve men and women with HIV (n=30) who are initiating abacavir/lamivudine/dolutegravir an ART regimen that is not associated with bone loss, in a comprehensive longitudinal study to compare the skeletal effects of the two ART regimens. We will evaluate bone density and strength using dual energy Xray absorptiometry (DXA) and High Resolution peripheral Quantitative CT (HRpQCT) with finite element analysis (Aim 1), obtain paired iliac-crest bone biopsies to evaluate histomorphometry and tissue-level mechanical properties using nanoindentation/ramen spectroscopy (Aim 2), and perform bone cell transcriptomics to explore underpinning molecular pathways. These studies are critical for development of safer ART options for long-term use in children with HIV to attain peak bone mass and in older adults with HIV to prevent fracture. This proposal leverages state-of-the art bone research techniques in a multidisciplinary collaboration of HIV and bone researchers from the U.S. and Brazil and provide opportunities for training to augment the bone research capacity at the University of São Paulo.

抽象的 骨质疏松症和骨折是HIV和抗逆转录病毒疗法（ART）的已知并发症。骨矿物质 在艺术计划后的第一年，密度（BMD）下降了2-4％，并且暴露于特定 诸如替诺福韦毒素（TDF）之类的艺术。艾滋病毒和与艺术相关的骨质流失的机制是 仍然不确定，因为缺乏组织级数据。通过哥伦比亚调查员之间的合作 圣保罗大学和大学具有完整的艾滋病毒和骨研究专业知识，我们能够 在12个月之前和12个月之前，对未经艺术的年轻人进行首次全面的纵向骨活检研究 在TDF/Lamivudine/Efavirenz主动启动之后。我们发现了骨形成和矿化的证据 艺术前异常。在艺术之后，骨细胞有所增加，但骨骼的持久性 矿化缺陷。我们的目标是注册未经艾滋病毒（n = 30）的成年男女 在全面 纵向研究比较了两种艺术方案的骨骼作用。我们将评估骨密度和 使用双能X射线绝对能力学（DXA）和高分辨率外周定量CT的强度 （HRPQCT）具有有限元分析（AIM 1），获得了配对的iLiac-Crest骨活检以评估 使用纳米识别/拉面光谱法（AIM 2），2）， 并执行骨细胞转录组学以探索基础分子途径。这些研究对于 开发艾滋病毒儿童长期使用的更安全的艺术选择，以达到峰值骨质量和年龄较大 患有艾滋病毒的成年人以防止骨折。该提议利用了最先进的骨研究技术 来自美国和巴西的艾滋病毒和骨骼研究人员的多学科合作，并提供机会 培训以增强圣保罗大学的骨研究能力。