Impact of HIV and antiretroviral initiation on skeletal biology

摘要 骨质疏松症和骨折是HIV和抗逆转录病毒疗法(ART)的已知并发症，但其机制 由于缺乏组织水平的数据，与艾滋病毒和抗逆转录病毒治疗相关的骨丢失仍不确定。在父母的资助中 (R21TW012367)，我们正在进行一项全面的纵向研究，以比较 两种抗逆转录病毒治疗方案(TDF/拉米夫定/法韦伦兹和拉米夫定/多洛替格韦)。我们将评估骨密度和 双能X线骨密度仪(DXA)和高分辨率外周定量CT的强度 (HRpQCT)与有限元分析(目标1)，获得成对的髂骨-冠骨活检以评估 使用纳米压痕/拉曼光谱的组织形态计量学和组织水平机械性能(目标2)， 并进行骨细胞转录，以探索支持分子途径。随着PWH年龄的增长，肾脏 损伤可能会增加，骨折的频率也会增加。蛋白尿与糖尿病之间的关系 骨质疏松症/骨折已经在艾滋病毒携带者和非HIV携带者中得到承认，尽管机制 尿蛋白丢失和骨脆性的基础尚未确定。特定的抗逆转录病毒药物，如 由于TDF导致近端肾小管功能障碍导致蛋白尿，但其他并存疾病和 传统因素也起到了作用。这本行政副刊提供了一个独特的机会来研究 巴西慢性骨质疏松症患者骨丢失中的蛋白尿。建立在艾滋病毒和骨骼的多学科合作基础上 来自美国和圣保罗S大学的研究人员在父母拨款中设立了这一补充 为老龄化相关研究提供更多的研究机会和能力建设，重点是 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