Impact of HIV and antiretroviral initiation on skeletal biology

摘要 骨质疏松和骨折是已知的艾滋病毒和抗逆转录病毒治疗(ART)的并发症。骨矿物质 密度(BMD)在ART开始后的第一年内下降2-4%，暴露于特定的 抗病毒药物，如富马酸替诺福韦(TDF)。人类免疫缺陷病毒和抗逆转录病毒治疗导致骨丢失的机制是 由于缺乏组织水平的数据，因此仍不确定。通过哥伦比亚大学调查人员之间的合作 S大学和圣保罗大学在艾滋病毒和骨骼研究方面的专业知识互补，我们能够 在艺术天真的年轻男性中进行第一次全面的纵向骨活检研究 在TDF/拉米夫定/法韦伦开始治疗后。我们发现了骨骼形成和矿化的证据 艺术面前的反常。ART术后，骨细胞密度增加，但在骨内持续存在。 矿化缺陷。我们的目标是招募成年艺术天真的艾滋病毒携带者(n=30)。 阿巴卡韦/拉米夫定/多洛替格韦：一种与骨丢失无关的ART疗法，在一项全面的 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。这些研究对于 HIV儿童和老年人长期使用ART以达到峰值骨量的更安全选择 成人携带艾滋病病毒，预防骨折。这项建议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S圣保罗大学的骨骼研究能力。

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.