Impact of HIV and antiretroviral initiation on skeletal biology

摘要 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，但其机制 由于缺乏组织水平的数据，HIV 和 ART 相关的骨质流失仍不确定。在家长补助金中 （R21TW012367），我们正在进行一项全面的纵向研究来比较 两种 ART 方案（TDF/拉米夫定/依非韦伦和拉米夫定/多替拉韦）。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。随着 PWH 年龄的增长，肾 损伤和骨折频率可能会增加。蛋白尿与蛋白尿之间的关系 骨质疏松/骨折在感染和未感染艾滋病毒的人中都已被认识到，尽管其机制 尿液中蛋白质流失和骨骼脆弱的基础尚未确定。特定的抗逆转录病毒药物，例如 因为 TDF 会导致近端肾小管功能障碍，从而导致蛋白尿，但其他并发症和的影响 传统因素也有影响。该行政补充提供了一个独特的机会来研究 巴西感染者骨质流失中的蛋白尿。以艾滋病毒和骨骼的多学科合作为基础 来自美国和圣保罗大学的研究人员在家长补助金中设立，该补充品将 为老龄化相关研究提供更多的研究和能力建设机会，重点关注 肾骨轴

ABSTRACT Osteoporosis and fractures are known complications of HIV and antiretroviral therapy (ART) but the mechanisms of HIV and ART associated bone loss are still uncertain because tissue-level data are lacking. In the parent grant (R21TW012367), we are performing a comprehensive longitudinal study to compare the skeletal effects of the two ART regimens (TDF/lamivudine/efavirenz and lamivudine/dolutegravir). 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. As PWH age, renal impairment is likely to increase as well as frequency of fracture. An association between proteinuria and osteoporosis/fracture has been recognized in people with and without HIV, although the mechanistic underpinnings of urinary loss of protein and bone fragility has not been established. Specific antiretrovirals, such as TDF cause proximal tubular dysfunction resulting in proteinuria but the effect of other co-morbidities and traditional factors also contribute. This administrative supplement offers a unique opportunity to study the role of proteinuria in bone loss among PWH in Brazil. Building upon the multidisciplinary collaboration of HIV and bone researchers from the U.S. and the University of São Paulo established in the parent grant, this supplement will provide additional opportunities for research and capacity building for aging-related research focusing on the kidney-bone axis