Impact of HIV and antiretroviral initiation on skeletal biology

摘要 骨质疏松症和骨折是艾滋病毒和抗逆转录病毒治疗（ART）的已知并发症。骨矿物质 在ART开始后的第一年内，骨密度（BMD）下降2-4%，并且随着暴露于特定的 ART，如富马酸替诺福韦酯（TDF）。艾滋病毒和ART相关骨质流失的机制是 因为缺乏组织水平的数据，所以仍然不确定。通过与哥伦比亚大学的研究人员合作 在艾滋病毒和骨骼研究方面具有互补专长的圣保罗大学和圣保罗大学，我们能够 在ART初治的年轻男性中进行首次全面的纵向骨活检研究， 开始TDF/拉米夫定/依法韦仑治疗后。我们发现了骨骼形成和矿化的证据 ART后，骨细胞增加，但骨细胞持续存在， 矿化缺陷我们的目标是招募接受过ART初治的成年HIV患者（n=30）， 阿巴卡韦/拉米夫定/度鲁特韦是一种与骨质流失无关的ART方案，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， 使用双能X线吸收测定法（DXA）和高分辨率外周定量CT进行强度检查 （HRpQCT）与有限元分析（目的1），获得配对髂嵴骨活检，以评估 使用纳米压痕/拉曼光谱法进行组织形态测量和组织水平机械性能（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疗法，长期用于艾滋病毒感染儿童，以达到峰值骨量， 艾滋病毒感染者预防骨折。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， 以加强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.