Molecular basis for HIV therapy-linked osteopenia

HIV治疗相关骨质减少的分子基础

• 批准号: 6893014
• 负责人: JEFFREY C LAURENCE
• 金额: $ 34.44万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893014
• 关键词: AIDS therapy; HIV envelope protein gp120; HIV infections; T lymphocyte; antiAIDS agent; cell differentiation; clinical research; cytokine receptors; drug adverse effect; human subject; interferon beta; interferon gamma; longitudinal human study; nuclear factor kappa beta; osteoclasts; osteopenia; pathologic bone resorption; patient oriented research; postmenopause; ritonavir; saquinavir; tissue /cell culture; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): HIV infection and its therapy are associated with disturbances in bone remodeling resulting in low bone mineral density (BMD). Bone remodeling is controlled within the bone microenvironment by interactions between T lymphocyte- and osteoblast-derived cytokines, specifically receptor activator of nuclear factor kappaB ligand (RANKL) and its decoy receptor osteoprotegerin. Although the mechanism of HIV-associated bone loss is not understood, we hypothesize that it results from disturbances in the regulation of osteoclastogenesis. We have demonstrated significantly greater osteoclast differentiation in peripheral blood mononuclear cells (PBMC) from HIV+ patients than HIV- controls. Moreover, we have observed significantly increased osteoclast activity in vitro utilizing PBMCs and sera from HIV+ patients treated with highly active antiretroviral therapies (HAART) that incorporate protease inhibitors (PI) that interfere with RANKL signaling compared to HAART regimens incorporating PIs that do not have this effect. We hypothesize that bone resorption is initiated in HIV infection by the synergistic influence on osteoclast precursors of two cytokines upregulated during the T cell activation characteristic of both anti-retroviral treatment of HIV and T cell exposure to HIV envelope gp120: RANKL and tumor necrosis factor (TNF)-alpha. We further hypothesize that this bone resorption may be accelerated by PIs which can abrogate at least one of two physiologic, interferon (IFN)-linked blocks to RANKL; activity. We will test these hypotheses using: (1) in vitro models for osteoclast differentiation and RANKL-driven signaling in peripheral blood and bone-derived precursors, as modified by HIV and anti-HIV PIs; and (2) cross-sectional and longitudinal analyses of HIV- and HIV+ postmenopausal women, the latter treatment-naive and on various HAART regimens.

描述（由申请人提供）：HIV 感染及其治疗与骨重塑紊乱相关，导致骨矿物质密度 (BMD) 低。骨重塑在骨微环境中通过 T 淋巴细胞和成骨细胞衍生的细胞因子，特别是核因子 kappaB 配体受体激活剂 (RANKL) 及其诱饵受体骨保护素之间的相互作用进行控制。尽管 HIV 相关骨质流失的机制尚不清楚，但我们假设它是由破骨细胞生成调节紊乱引起的。我们已经证明，与 HIV 对照者相比，HIV 阳性患者的外周血单核细胞 (PBMC) 中的破骨细胞分化显着增强。此外，我们观察到，与含有干扰 RANKL 信号传导的蛋白酶抑制剂 (PI) 的高活性抗逆转录病毒疗法 (HAART) 治疗的 HIV + 患者的 PBMC 和血清相比，与含有不含有此功能的 PI 的 HAART 方案相比，体外破骨细胞活性显着增加影响。我们假设，在 HIV 感染中，骨吸收是通过对 HIV 抗逆转录病毒治疗的 T 细胞激活特征和 T 细胞暴露于 HIV 包膜 gp120：RANKL 和肿瘤坏死因子期间上调的两种细胞因子对破骨细胞前体的协同影响而启动的。 TNF)-α。我们进一步假设，PI 可能会加速这种骨吸收，PI 可以消除 RANKL 的两种生理性干扰素 (IFN) 相关阻断中的至少一种；活动。我们将使用以下方法测试这些假设：(1) 破骨细胞分化的体外模型以及外周血和骨源性前体中 RANKL 驱动的信号传导，经 HIV 和抗 HIV PI 修改； (2) 对 HIV 感染和 HIV+ 绝经后妇女进行横断面和纵向分析，后者未经治疗且接受各种 HAART 方案。