HIV 1 Alters Mesenchymal Stem Cell Differentiation Potential and Cell Phenotype ex Vivo
HIV 1 Alters Mesenchymal Stem Cell Differentiation Potential and Cell Phenotype ex Vivo
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DOI：
10.1089/aid.2010.0114
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发表时间：
2011-02-01
影响因子：
1.5
通讯作者：
Doran, Peter P.
中科院分区：
文献类型：
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作者：
Cotter, Eoin J.;Chew, Nicholas;Doran, Peter P.
骨和脂质毒性发生率的增加与HIV-1感染及其治疗有关。间充质干细胞（MSCs）是一种多能细胞，可以分化为成骨细胞（OB）和脂肪细胞（AC）。我们假设MSC和HIV-1的相互作用是这些毒性的基础。血清采集于未感染对照和hiv感染、抗病毒初治患者。血清分为hiv阴性血清（n =5）、hiv阳性低病毒载量（LVL） （VL范围为120；4000,n=5）和高病毒载量（HVL） （VL范围为10万；50万，n=5）三组。在急性和慢性暴露模型中，MSCs在成脂/成骨条件和非分化条件下暴露于这些血清（5%）。在诱导分化细胞和非分化细胞的MSCs中检测脂肪生成/成骨标志物。HVL hiv -1感染个体的血清诱导了明显的前脂肪形成表型，这可以通过脂肪细胞形成增加和诱导包括LPL和PPAR γ在内的脂肪生成标记物表达增加来证明。CD4受体阻断和抗逆转录病毒AZT治疗都减弱了这些致脂肪作用，表明感染事件可能是观察到的现象的基础。最后，HIV-1 TAT对COUP TF-1的抑制被确定为这些效应的潜在分子机制。这些结果表明，HIV-1直接与MSCs相互作用并可能感染MSCs，导致其分化潜力的改变，这些发现显著增强了我们对HIV-1相关的骨和脂肪毒性的理解。
An increased incidence of bone and lipid toxicities is associated with HIV-1' infection and its treatment. Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into both osteoblasts (OB) and adipocytes (AC). We hypothesize that the interaction of MSC and HIV-1 underlie these toxicities. Serum was collected from uninfected control and HIV-infected, antiviral-naive patients. Sera were divided into three groups: HIV-negative sera (n = 5), HIV-positive low viral load (LVL) (VL range 120; 4000, n=5) or high viral load (HVL) (VL range 100,000; 500,000, n = 5). MSCs were exposed to these sera (5%) in an adipogenic/osteogenic condition and in nondifferentiating conditions in acute and chronic exposure models. Markers of adipogenesis/osteogenesis were examined in both MSCs induced to differentiated and nondifferentiating cells. Sera from HVL HIV-1-infected individuals induced a clear proadipogenic phenotype, as evidenced by an increase in adipocyte formation and the induction of increased expression of adipogenic markers including LPL and PPAR gamma. Both CD4 receptor blockade and treatment with the antiretroviral AZT attenuated these proadipogenic effects, suggesting that an infection event may underlie the observed phenomena. Finally, inhibition of COUP TF-1 by HIV-1 TAT was identified as a potential molecular mechanism for these effects. These results suggest that HIV-1 directly interacts with and may infect MSCs resulting in alterations of their differentiation potential, findings that significantly enhance our understanding of HIV-1-associated bone and fat toxicities.