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

描述（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。虽然大多数的神经系统并发症的艾滋病毒感染的发病率已显着下降，使用这些药物治疗方案，周围神经病变（PN），一个毁灭性的并发症核苷逆转录酶抑制剂（NRTI）治疗，是越来越常见的艾滋病毒/艾滋病患者。PN中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，导致氧化应激的药物诱导的线粒体异常和营养不良。铁代谢在HIV感染中是异常的，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中的作用尚未直接探讨。血色素沉着症（HFE）基因C282 Y的一种常见变异导致膳食铁吸收增加，细胞铁转运和免疫缺陷。HFE编码的铁转运蛋白在巨噬细胞上的表达最近被证明是HIV-1感染的结果。我们之前使用了来自艾滋病临床试验组（ACTG）进行的一项大型前瞻性队列研究的临床数据和储存的DNA，以进行开创性的观察，即HFE C282 Y可在HIV/AIDS的NRTI治疗期间防止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HIV/AIDS破坏的人群中流行，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，我们研究的目的是在同一HIV队列中使用冷冻保存的血清样本，以确定1）HFE C282 Y携带者中PN减少是否是由于体内铁储存增加，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相关，3）如果统计模型包含铁储存，NRTI治疗期间铁水平的早期变化; HFE基因型和某些高危线粒体DNA变异可以预测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R 01赠款申请提供关键的初步数据，以资助深入的机制研究，我们希望这些研究最终能够使临床医生减少艾滋病毒/艾滋病治疗中这种使人衰弱的并发症的发生率。

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.