Mitochondrial Genomics and Peripheral Neuropathy during HIV Therapy

描述(申请人提供)：有效的抗逆转录病毒疗法(ART)，包括核苷逆转录酶抑制剂(NRTI)，可显著降低因人类免疫缺陷病毒1型(HIV)感染和获得性免疫缺陷综合征(AIDS)而导致的发病率和死亡率，但往往受到线粒体毒性的限制。周围神经病(PN)是一种常见的、使人虚弱的毒性，通常是不可逆转的。NRTI相关性PN的发病、特征和严重程度的变化强烈表明宿主遗传学在其中起作用，但对这种作用的理解一直难以捉摸。随着拯救生命的抗逆转录病毒药物在资源有限的环境中越来越多地可用，我们可以预见未来PN在新人群中的“流行”，除非改进的理解和技术能够迅速转化为这些环境。这项建议的主要假设是，通过应用最先进的技术(高通量全线粒体基因组测序)和计算资源(包括多因素降维)，改善对人类线粒体基因组变异和ART诱导的PN之间的关联的理解，可以防止这种毒性，并最终改善长期的ART结果。这项拟议的工作将扩展现有的关于ART对线粒体影响的知识基础，并将通过解决两个具体目标来探索新的领域：1)表征线粒体DNA(MtDNA)多态，包括多位点遗传相互作用，使接受NRTI-ART治疗的HIV感染者更容易发生症状性PN；以及2)表征mtDNA多态与神经元和线粒体损伤标记物之间的关系，包括表皮神经纤维密度、血清乳酸浓度和外周血mtDNA含量。我们建议通过使用储存的DNA和800名HIV感染临床研究参与者的可用数据进行嵌套病例对照研究来解决这些目标。来自这些研究的信息将使临床医生能够更好地个体化艾滋病毒治疗，避免虚弱的、往往是不可逆转的和昂贵的并发症，从而在世界上富裕和资源有限的地区都有重要的应用。这项研究的结果还将推动“线粒体医学”领域的发展，在其他科学学科和其他人类疾病中有广泛的应用。

DESCRIPTION (provided by applicant): Potent antiretroviral therapy (ART) including nucleoside reverse transcriptase inhibitors (NRTI) substantially reduces morbidity and mortality due to human immunodeficiency virus type 1 (HIV) infection and acquired immunodeficiency syndrome (AIDS), but is frequently limited by mitochondrial toxicity. Peripheral neuropathy (PN) is a common, debilitating toxicity that is often irreversible. Variation in the onset, character, and severity of NRTI-associated PN strongly suggests host genetics play a role, but an understanding of this role has been elusive. As life-saving ART becomes increasingly available in resource-limited settings, we can anticipate a future "epidemic" of PN in new populations unless improved understanding and technology can be rapidly translated to these settings. The overarching hypothesis of this proposal is that improved understanding of associations between variation in the human mitochondrial genome and ART-induced PN through the application of state-of-the-art technology (high- throughput whole mitochondrial genome sequencing) and computational resources (to include multifactor dimensionality reduction) can prevent this toxicity and ultimately improve long-term ART outcomes. The proposed work will expand on the existing base of knowledge regarding mitochondrial effects of ART, and will explore novel areas by addressing two specific aims: 1) To characterize mitochondrial DNA (mtDNA) polymorphisms, including multilocus genetic interactions, that confer increased susceptibility to the development of symptomatic PN among HIV-infected individuals treated with NRTI-containing ART regimens; and 2) To characterize relationships between mtDNA polymorphisms and markers of neuronal and mitochondrial injury, including epidermal nerve fiber densities, serum lactate concentrations, and peripheral blood mtDNA content. We propose to address these aims through nested case-control studies using stored DNA and available data from 800 HIV-infected clinical study participants. Information from these studies will allow clinicians to better individualize HIV therapy, avoiding debilitating, often irreversible, and costly complications, thus having important applications in both affluent and resource-limited parts of the world. Results from this study will also advance the field of "mitochondrial medicine", having broad application across other scientific disciplines and for other human diseases.