Mitochondrial Heteroplasmy as an Endophenotype of HIV-Associated Neurocognitive Disorders

摘要 HIV相关神经认知障碍（HAND）和其他与衰老相关的退行性和代谢性疾病 尽管有抗逆转录病毒治疗，但艾滋病毒感染者（PLWH）中的疾病发生率过高 治疗和病毒学抑制。细胞内能量发生器（线粒体）的功能异常， 在这些复杂的疾病中起重要作用，但这些异常的基础在很大程度上是未知的。 虽然遗传性线粒体DNA（mtDNA）突变与复杂的人类疾病有关， 在个体的一生中获得的mtDNA突变的影响才刚刚开始出现， 下一代DNA测序技术的力量，这是必不可少的检测。存在 一个个体的每个细胞内有多个mtDNA拷贝（因此有许多共存的mtDNA类型）定义了 线粒体异质性和低频率的致病性，以及常见的异质性突变 随着年龄的增长，即使在健康个体中，也可能会超过引起疾病的组织特异性阈值。 一些研究表明，在HIV感染过程中，mtDNA突变增加和/或预先存在的异质性扩大。 感染和慢性治疗。异质性与认知障碍及其他疾病的关系 都是在艾滋病环境之外进行的。这项建议将探讨线粒体异质性在 手，以及它与已知的老化和手的相关性。更好地了解这些 这种关系可能会导致新的风险监测和治疗策略，旨在改善线粒体 功能和降低PLWH中HAND的风险。我们建议利用一项独特的纵向老化研究 在艾滋病毒携带者和艾滋病毒阴性对照人群中开展的活动，以实现以下具体目标： 1)抗逆转录病毒治疗的PLWH患者12年期间mtDNA异质性变化的比较 2a）确定mtDNA异质性与生物标志物之间的关系 PLWH患者的脑脊液炎症、氧化应激和全身铁状态对抑制 抗逆转录病毒治疗;和2b）确定mtDNA异质性与mtDNA拷贝数的关联， 在PLWH的横截面和纵向分析的神经认知性能的措施。为此目的， 100名PLWH和25名年龄匹配的HIV血清阴性个体将接受mtDNA的深度测序， 在基线和10-12年随访时测量mtDNA拷贝数。异质性关联 还将在PLWH中进行测量的铁状态和现有的年龄和氧化应激生物标志物。的 我们为此目的组建的团队拥有最先进的下一代测序方法的专业知识， 在大型队列中的mtDNA异质性研究，以及神经炎症和 手

ABSTRACT HIV-Associated Neurocognitive Disorders (HAND) and other aging-related degenerative and metabolic disorders occur with excess frequency among people living with HIV infection (PLWH), despite antiretroviral therapy and virologic suppression. Abnormal function of energy generators within cells (mitochondria) plays an important role in these complex disorders, but the basis for these abnormalities is, for the most part, unknown. While inherited mitochondrial DNA (mtDNA) mutations have been studied in relation to complex human diseases, the impact of mtDNA mutations acquired over the lifespan of an individual is only just beginning to emerge, due to the power of next-generation DNA sequencing technologies that are essential for their detection. The presence of multiple mtDNA copies within each cell in an individual (and hence many coexisting types of mtDNA) defines mitochondrial heteroplasmy, and low-frequency pathogenic, as well as common heteroplasmic mutations increase with age, even in healthy individuals, potentially crossing tissue-specific thresholds for causing disease. Some studies suggest increased mtDNA mutations and/or expansion of pre-existing heteroplasmies during HIV infection and chronic treatment. Associations between heteroplasmy and cognitive disorders and other diseases have been made outside the HIV setting. This proposal will investigate the role of mitochondrial heteroplasmy in HAND, as well as its association with known correlates of aging and HAND. A better understanding of these relationships may lead to novel risk-monitoring and treatment strategies aimed at improving mitochondrial function and reducing the risk of HAND in PLWH. We propose to leverage a unique, longitudinal aging study among PLWH, and a similarly selected HIV(-) comparison population to implement the following Specific Aims: 1) Compare changes in mtDNA heteroplasmy over a 12-year period between PLWH on antiretroviral therapy and HIV-seronegative individuals; 2a) Determine relationships between mtDNA heteroplasmy and biomarkers of cerebrospinal-fluid inflammation, oxidative stress, and systemic iron status in PLWH on suppressive antiretroviral therapy; and 2b) Determine associations of mtDNA heteroplasmy with mtDNA copy number and measures of neurocognitive performance in cross-sectional and longitudinal analyses in PLWH. For this purpose, 100 PLWH and 25 age-matched HIV-seronegative individuals will undergo deep sequencing of mtDNA and measurement of mtDNA copy number at baseline and 10-12-yr follow-up visits. Heteroplasmy associations with measured iron status and existing age- and oxidative stress biomarkers will also be performed in PLWH. The team we have assembled for this purpose has expertise in state-of-the-art next-generation sequencing methods, mtDNA heteroplasmy studies in large cohorts, and in iron-mitochondrial genomics of neuroinflammation and HAND.