Ofotokun Ighovwerha, Titanji Kehmia, Vunnava Aswani, Roser-Page Susanne, Vikulina Tatyana, Villinger Francois, Rogers Kenneth, Sheth Anandi N, Lahiri Cecile Delille, Lennox Jeffrey L, Weitzmann M Neale
aDivision of Infectious Diseases, Department of Medicine, Emory University School of Medicine and Grady Healthcare System bDivision of Endocrinology and Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta cAtlanta Department of Veterans Affairs Medical Center, Decatur dDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine eDivision of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA. *Ighovwerha Ofotokun, Kehmia Titanji and Aswani Vunnava have contributed equally as first authors. †Ighovwerha Ofotokun and M. Neale Weitzmann have contributed equally to this work as lead investigators.
AIDS. 2016 Jan 28;30(3):405-14. doi: 10.1097/QAD.0000000000000918.
Antiretroviral therapy (ART) paradoxically intensifies bone loss in the setting of HIV infection. Although the extent of bone loss varies, it occurs with virtually all ART types, suggesting a common pathway that may be aligned with HIV disease reversal. Using an animal model of immunodeficiency we recently demonstrated that immune activation associated with CD4 T-cell reconstitution induces increased production of the osteoclastogenic cytokines RANKL and TNFα by immune cells, driving enhanced bone resorption and loss in bone mineral density.
To confirm these findings in humans, we investigated the early kinetics of CD4 T-cell recovery in relation to biomarkers of bone turnover and osteoclastogenic regulators in a prospective 24-week cohort study.
Clinical data and blood sampling for HIV-RNA PCR, CD4 T-cell counts, bone turnover biomarkers, and osteoclastogenic regulators were obtained from ART-naïve HIV-infected study participants initiating standard doses of lopinavir/ritonavir plus tenofovir disoproxil fumarate/emtricitabine at baseline and at weeks 2, 8, 12, and 24 post ART.
C-terminal telopeptide of collagen (CTx) a sensitive biomarker of bone resorption rose by 200% above baseline at week 12, remaining elevated through week 24 (α<0.01), and was associated with significant increases in plasma levels of osteoclastogenic regulators [receptor activator of NF-kB ligand (RANKL), tumor necrosis factor alpha, (TNFα)]. Importantly, the magnitude of CD4 T-cell recovery correlated significantly with CTx (rs = 0.387, α=0.01).
Our data suggest that ART-induced bone loss occurs early, is aligned with early events of immune reconstitution, and these immune changes provide a unifying mechanism to explain in part the skeletal decline common to all ART.
在人类免疫缺陷病毒（HIV）感染的情况下，抗逆转录病毒疗法（ART）反常地加剧骨质流失。尽管骨质流失的程度各不相同，但几乎所有类型的ART都会出现这种情况，这表明可能存在一条与HIV疾病逆转相关的共同途径。我们最近使用免疫缺陷动物模型证明，与CD4 T细胞重建相关的免疫激活会诱导免疫细胞增加破骨细胞生成细胞因子RANKL和TNFα的产生，从而导致骨吸收增强和骨矿物质密度降低。
为了在人类中证实这些发现，我们在一项为期24周的前瞻性队列研究中，研究了CD4 T细胞恢复的早期动力学与骨转换生物标志物和破骨细胞生成调节因子之间的关系。
从初治HIV感染的研究参与者中获取临床数据以及用于HIV-RNA PCR、CD4 T细胞计数、骨转换生物标志物和破骨细胞生成调节因子的血液样本，这些参与者在基线以及ART后第2、8、12和24周开始使用标准剂量的洛匹那韦/利托那韦加替诺福韦酯/恩曲他滨。
骨吸收的敏感生物标志物——胶原C末端肽（CTx）在第12周时比基线水平升高了200%，并在第24周时一直保持升高（α<0.01），且与破骨细胞生成调节因子[核因子κB受体活化因子配体（RANKL）、肿瘤坏死因子α（TNFα）]的血浆水平显著升高相关。重要的是，CD4 T细胞恢复的幅度与CTx显著相关（rs = 0.387，α = 0.01）。
我们的数据表明，ART诱导的骨质流失发生得很早，与免疫重建的早期事件相关，并且这些免疫变化提供了一种统一的机制，部分解释了所有ART共同导致的骨骼衰退。
