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 和抗逆转录病毒治疗 (ART) 的已知并发症。骨矿物质 开始 ART 后的第一年内，密度 (BMD) 下降 2-4%，并且随着暴露于特定的 ART，例如富马酸替诺福韦二吡呋酯 (TDF)。 HIV 和 ART 相关骨质流失的机制是 仍然不确定，因为缺乏组织水平的数据。通过哥伦比亚大学研究人员之间的合作 大学和圣保罗大学在艾滋病毒和骨骼研究方面具有互补的专业知识，我们能够 在之前和 12 个月内对未接受过 ART 的年轻男性进行首次全面纵向骨活检研究 开始 TDF/拉米夫定/依非韦伦后。我们发现了骨形成和矿化的证据 ART 前的异常。 ART 后，骨细胞结构有所增加，但骨结构持续存在 矿化缺陷。我们的目标是招募未接受过 ART 治疗且正在开始接受 ART 治疗的成年 HIV 感染者 (n=30) 阿巴卡韦/拉米夫定/多替拉韦是一种与骨质流失无关的 ART 治疗方案，综合考虑 纵向研究比较两种 ART 方案对骨骼的影响。我们将评估骨密度并 使用双能 X 射线吸收测定法 (DXA) 和高分辨率外周定量 CT 测定强度 (HRpQCT) 与有限元分析（目标 1），获得成对的髂嵴骨活检以进行评估 使用纳米压痕/拉面光谱进行组织形态测量和组织级机械性能（目标 2）， 并进行骨细胞转录组学以探索基础分子途径。这些研究对于 开发更安全的抗逆转录病毒治疗方案，供艾滋病毒感染儿童和老年人长期使用，以达到骨量峰值 感染艾滋病毒的成年人可预防骨折。该提案利用了最先进的骨骼研究技术 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 接受培训以增强圣保罗大学的骨骼研究能力。