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

描述(由申请人提供)：获得高活性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。虽然随着这些药物方案的使用，HIV感染的大多数神经系统并发症的发生率已经显著下降，但作为核苷逆转录酶抑制剂(NRTI)治疗的破坏性并发症，周围神经病(PN)在艾滋病毒/艾滋病患者中越来越常见。PN中神经损伤的确切机制尚不清楚，但重要的因素包括：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，以及营养不良。铁的代谢在HIV感染中是异常的，但铁作为一种对线粒体和神经功能至关重要的微量营养素，在HIV相关的PN中的作用尚未被直接探讨。血色素沉着症(HFE)基因的一种常见变异C282Y会导致饮食中铁吸收增加，并导致细胞铁运输和免疫缺陷。最近，由于HIV-1感染，巨噬细胞上HFE编码的铁运输蛋白的表达减少。我们之前使用了由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，以进行开创性的观察，即HFE C282Y在艾滋病毒/艾滋病的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，而且在许多被艾滋病毒/艾滋病摧毁的人群中，缺铁是地方性疾病，因此确定这种保护作用的机制至关重要，以便使全球患者受益。因此，我们研究的目标是利用同一HIV队列中深低温保存的血清样本来确定1)HFE C282Y携带者的PN减少是否是由于体内铁存储增加；2)NRTI治疗期间PN的发病时间是否与开始治疗之前或之后的铁水平有关；3)如果一个统计模型包含铁存储，则可以创建一个包含NRTI治疗期间铁水平早期变化的统计模型；HFE基因和某些高危线粒体DNA变体可以创建来预测PN的发展。将使用传统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，我们希望这些研究最终将使临床医生能够减少艾滋病毒/艾滋病治疗中这种令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.