Iron as Nutritional Modifier Toxic Neuropathy HIV/AIDS

铁作为营养调节剂 毒性神经病 艾滋病毒/艾滋病

• 批准号: 7230736
• 负责人: ASHA R KALLIANPUR
• 金额: $ 15.31万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230736
• 关键词: AIDS /HIV neuropathy; HIV infections; antiAIDS agent; clinical research; disease /disorder onset; drug adverse effect; ferritin; genetic polymorphism; genotype; hemosiderosis; human immunodeficiency virus 1; human subject; iron metabolism; iron storage disorder; mathematical model; membrane proteins; microcytic /hypochromic anemia; mitochondrial DNA; neuroprotectants; pharmacogenetics; reverse transcriptase inhibitors; transferrin receptor

DESCRIPTION (provided by applicant): Access to highly active anti-retroviral drug therapy has markedly reduced morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). Although the incidence of most of the neurological complications of HIV infection has declined dramatically with the use of these drug regimens, peripheral neuropathy (PN), a devastating complication of nucleoside reverse transcriptase inhibitor (NRTI) therapy, is increasingly common among persons living with HIV/AIDS. The precise mechanisms of nerve damage in PN are unclear, but important factors include: nerve inflammation caused by HIV-infected macrophages, drug-induced mitochondrial abnormalities leading to oxidative stress, and poor nutrition. Iron metabolism is abnormal in HIV infection, but the role of iron, a micronutrient critical for mitochondrial and neuronal function, has not been directly explored in HIV-associated PN. A common variant in the hemochromatosis (HFE) gene, C282Y, causes increased dietary iron absorption and defects in cellular iron transport and immunity. Expression of the HFE-encoded iron-transport protein on macrophages has recently been shown to decrease as result of HIV-1 infection. We previously used clinical data and stored DNA from a large, prospective cohort study conducted by the AIDS Clinical Trials Group (ACTG) to make the seminal observation that HFE C282Y protects against the development of PN during NRTI therapy in HIV/AIDS. Since this iron-loading variant is protective against PN, and iron deficiency is endemic in many populations devastated by HIV/AIDS, it is critical to define the mechanism underlying this protective effect in order to benefit patients globally. The goals of our study are therefore to use cryopreserved serum samples in the same HIV cohort to determine 1) if reduced PN in HFE C282Y carriers is due to increased body iron stores, 2) if time to onset of PN during NRTI therapy is related to iron levels before or soon after starting treatment, 3) if a statistical model incorporating iron stores, early changes in iron levels during NRTI therapy; HFE genotype, and certain high-risk mitochondrial DNA variants can be created to predict the development of PN. Conventional regression as well as newer statistical modeling tools will be used. These studies will generate critical preliminary data for an R01 grant application to fund in-depth mechanistic studies that we hope will ultimately enable clinicians to reduce the incidence of this debilitating complication of HIV/AIDS treatment.

描述（由申请人提供）：获得高效抗逆转录病毒药物治疗显着降低了与获得性免疫缺陷综合症（艾滋病）相关的发病率和死亡率。尽管随着这些药物治疗方案的使用，大多数 HIV 感染神经系统并发症的发生率已显着下降，但周围神经病变 (PN)（核苷逆转录酶抑制剂 (NRTI) 治疗的一种破坏性并发症）在 HIV 感染者中越来越常见/艾滋病。 PN 神经损伤的确切机制尚不清楚，但重要因素包括：HIV 感染巨噬细胞引起的神经炎症、药物引起的线粒体异常导致氧化应激以及营养不良。 HIV 感染时铁代谢异常，但铁（一种对线粒体和神经元功能至关重要的微量营养素）在 HIV 相关 PN 中的作用尚未得到直接探索。血色素沉着症 (HFE) 基因 C282Y 的常见变异会导致膳食铁吸收增加以及细胞铁转运和免疫缺陷。最近显示，巨噬细胞上 HFE 编码的铁转运蛋白的表达会因 HIV-1 感染而减少。我们之前使用了 AIDS 临床试验组 (ACTG) 进行的一项大型前瞻性队列研究的临床数据和存储的 DNA，进行了开创性的观察，即 HFE C282Y 在 HIV/AIDS 的 NRTI 治疗期间可防止 PN 的发展。由于这种载铁变体可以预防 PN，并且铁缺乏症在许多遭受 HIV/AIDS 破坏的人群中普遍存在，因此确定这种保护作用背后的机制至关重要，以便使全球患者受益。因此，我们研究的目标是使用同一 HIV 队列中的冷冻保存血清样本来确定 1) HFE C282Y 携带者 PN 减少是否是由于体内铁储备增加所致，2) NRTI 治疗期间 PN 发作时间是否与以下因素相关：开始治疗前或治疗后不久的铁水平，3) 如果统计模型包含铁储存，则 NRTI 治疗期间铁水平的早期变化；可以创建 HFE 基因型和某些高风险线粒体 DNA 变异来预测 PN 的发展。将使用传统的回归以及更新的统计建模工具。这些研究将为 R01 拨款申请提供重要的初步数据，以资助深入的机制研究，我们希望这些研究最终使临床医生能够减少这种令人衰弱的艾滋病毒/艾滋病治疗并发症的发生率。