Iron as a Nutritional Modifier of Toxic Neuropathy in HIV/AIDS

铁作为艾滋病毒/艾滋病中毒性神经病的营养调节剂

• 批准号: 7295817
• 负责人: ASHA R KALLIANPUR
• 金额: $ 14.9万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7295817
• 关键词: AIDS clinical trial group; Acquired Immunodeficiency Syndrome; Address; Adverse effects; Anti-Retroviral Agents; Applications Grants; Carrier Proteins; Cells; Chronic; Clinical Data; Clinical Trials Cooperative Group; Cohort Studies; Complication; Comprehensive Health Care; Computational Technique; Confidence Intervals; DNA; DNA Library; Data; Defect; Depth; Development; Dideoxynucleosides; Dietary Iron; Disease; Disease regression; Drug usage; Environmental Risk Factor; Ferritin; Follow-Up Studies; Funding; Genes; Genetic Polymorphism; Genotype; Goals; HIV; HIV Infections; HIV Seropositivity; HIV-1; Haplogroup; Hemochromatosis; Heterozygote; Immunity; Incidence; Individual; Infection; Inflammation; Inflammatory; Iron; Life; Linear Regressions; Logistic Regressions; Malnutrition; Methods; Micronutrients; Mitochondria; Mitochondrial DNA; Modeling; Morbidity - disease rate; Nerve; Neurodegenerative Disorders; Neurologic; Neurons; Neuropathy; Nucleosides; Nutritional; Other Genetics; Oxidative Stress; Participant; Patients; Peripheral Nervous System Diseases; Persons; Pharmaceutical Preparations; Pharmacotherapy; Play; Population; Predisposition; Proteins; Recycling; Research Personnel; Reverse Transcriptase Inhibitors; Risk; Risk Factors; Role; Sampling; Seminal; Serum; Serum iron level result; Statistical Models; Testing; Time; Toxic effect; Transferrin Receptor; Treatment Protocols; United States National Institutes of Health; Variant; absorption; case control; cohort; hazard; indexing; iron metabolism; macrophage; mitochondrial dysfunction; mortality; nef Protein; novel; nutrition; predictive modeling; programs; prospective; protective effect; tool

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著降低了与获得性免疫缺陷综合征（艾滋病）相关的发病率和死亡率。尽管随着这些药物方案的使用，大多数艾滋病毒感染的神经系统并发症的发生率急剧下降，但核苷逆转录酶抑制剂（NRTI）治疗的破坏性并发症——周围神经病变（PN）在艾滋病毒/艾滋病患者中越来越普遍。PN神经损伤的确切机制尚不清楚，但重要的因素包括：hiv感染巨噬细胞引起的神经炎症、药物诱导的线粒体异常导致氧化应激和营养不良。铁代谢在HIV感染中异常，但铁作为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中的作用尚未直接探讨。血色素沉着症（HFE）基因的一种常见变体C282Y导致膳食铁吸收增加和细胞铁运输和免疫缺陷。最近研究表明，由于HIV-1感染，巨噬细胞中fe编码铁转运蛋白的表达减少。我们之前使用了艾滋病临床试验小组（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NRTI治疗HIV/AIDS期间可以防止PN的发展。由于这种铁负载变体对PN具有保护作用，并且铁缺乏在许多受艾滋病毒/艾滋病破坏的人群中普遍存在，因此确定这种保护作用的机制以使全球患者受益至关重要。因此，我们的研究目标是在同一HIV队列中使用冷冻保存的血清样本，以确定1)HFE C282Y携带者的PN减少是否由于体内铁储量增加，2)NRTI治疗期间PN发作的时间是否与开始治疗前或开始治疗后不久的铁水平有关，3)如果统计模型包含铁储量，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较新的统计建模工具。这些研究将为R01拨款申请提供关键的初步数据，以资助深入的机制研究，我们希望最终能够使临床医生减少这种使人衰弱的HIV/AIDS治疗并发症的发生率。