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）：获得高度活跃的抗逆转录病毒药物疗法的机会显着降低了与获得的免疫缺陷综合征（AIDS）相关的发病率和死亡率。尽管大多数HIV感染的神经系统并发症的发生率随使用这些药物方案而急剧下降，但周围神经病（PN）是核苷逆转录酶抑制剂（NRTI）疗法的毁灭性并发症，在患有HIV/AIDS的患者中越来越普遍。 PN神经损伤的确切机制尚不清楚，但重要因素包括：由HIV感染的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感染中是异常的，但是铁（一种对线粒体和神经元功能至关重要的微量营养素的作用）尚未在与HIV相关的PN中直接探索。血色素肿瘤（HFE）基因C282Y中的常见变异，导致饮食中的铁吸收和细胞铁转运和免疫力的缺陷增加。 HFE编码的铁传输蛋白在巨噬细胞上的表达最近已显示由于HIV-1感染而降低。我们先前使用了临床数据并存储了由AIDS临床试验组（ACTG）进行的大型前瞻性队列研究中的DNA，以使HFE C282Y预防HIV/AIDS NRTI治疗期间的PN发展。由于这种铁负载变体对PN具有保护性，并且在许多受HIV/AIDS破坏的人群中，铁缺乏症是特有的，因此定义这种保护作用的机制至关重要，以使全球患者受益。 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;可以创建HFE基因型和某些高风险线粒体DNA变体来预测PN的发展。将使用常规回归以及新的统计建模工具。这些研究将为R01赠款应用提供关键的初步数据，以资助深入的机械研究，我们希望最终使临床医生能够减少这种使HIV/AIDS治疗的衰弱并发症的发生率。