Iron Dysregulation and Neuropsychiatric Complications of HIV Across the Lifespan: Impact of Biologic Factors, Antiretroviral Therapy and Genetics

摘要 艾滋病毒感染者患抑郁症和神经认知障碍（NCI）的患病率更高 这些疾病经常同时发生，降低了药物依从性和质量 死亡率增加了至少两倍对大量女性和男性的研究迫切需要 需要阐明这些疾病的神经生物学机制以及最近确定的性别， 脆弱性的差异。小胶质细胞介导的神经炎症和犬尿氨酸通路的改变 (KP)，其对于维持平衡的单胺神经递质（例如，多巴胺和血清素） 在大脑中的合成，都与这两种疾病有关。铁，由艾滋病毒和抗逆转录病毒组合失调 cART治疗密切参与小胶质细胞活化、KP和神经递质代谢。我们 在单个神经-HIV队列和HIV（-）人群中的初步研究表明， 抑郁症和NCI中的铁代谢和铁相关基因网络，以及性别特异性效应。的 拟议的研究利用了来自三个大型组织的现有临床，铁生物标志物和全基因组数据集。 前瞻性艾滋病毒队列研究，以有力和全面地询问铁在抑郁症中的作用， 两性均为NCI。血清和脑脊液（CSF）生物标志物的组合，以铁为中心的全基因组 协会和网络生物信息学方法将被采用。这一建议的主要假设是 铁失调和铁相关基因/网络是PWH中抑郁和NCI的主要贡献者， 总体风险的变异性部分由年龄、性别、HIV和cART对铁的影响解释。具体目标是： 1)确定铁稳态改变在不同年龄范围的PWH抑郁症和NCI中的作用， 可归因于生物因素、HIV和cART对铁的影响的易感性比例; 2） 确定与铁代谢相关的新的铁依赖途径、铁代谢基因和铁数量性状基因座 抑郁症和NCI在女性和男性艾滋病毒感染者，并确定这些遗传效应的程度， 3）探索网络优先的铁相关基因敲低对铁介导的功能性影响， 使用体外HIV（+/-）人小胶质细胞模型生产KP代谢物。此外，Aim 1将与 铁指数在一个子集的个人CSF单胺代谢物。我们希望这些研究能够取得进展 了解导致艾滋病毒感染者抑郁和NCI的机制，这表明新的精确性- 疾病管理的医学方法和潜在的影响，铁或KP调节干预措施。

ABSTRACT People with HIV experience a much higher prevalence of depression and neurocognitive impairment (NCI) than the general population, and these disorders frequently co-occur, reducing medication adherence and quality of life and increasing mortality at least two-fold. Studies with large numbers of women as well as men are urgently needed to elucidate the neurobiologic mechanisms underlying these disorders as well as recently identified sex differences in vulnerability. Microglia-mediated neuro-inflammation and alterations in the Kynurenine Pathway (KP), which is essential for maintaining balanced mono-amine neurotransmitter (e.g., dopamine and serotonin) synthesis in the brain, are implicated in both disorders. Iron, dysregulated by HIV and combination antiretroviral therapy (cART), is intimately involved in microglial activation, the KP, and neurotransmitter metabolism. Our preliminary studies in a single neuro-HIV cohort and in HIV(-) persons indicate a significant role for dysregulated iron metabolism and iron-related gene networks in depression and NCI, as well as sex-specific effects. The proposed study leverages existing clinical, iron-biomarker, and genome-wide datasets from three large prospective HIV cohort studies to powerfully and comprehensively interrogate the role of iron in depression and NCI in both sexes. A combination of serum and cerebrospinal-fluid (CSF) biomarker, iron-centered genome-wide associations, and network bioinformatics approaches will be employed. Central hypotheses of this proposal are that iron dysregulation, and iron-related genes/networks, are major contributors to depression and NCI in PWH, with variability in overall risk explained in part by age, sex, HIV, and cART effects on iron. The Specific Aims are: 1) Determine the role of altered iron homeostasis in depression and NCI in PWH across the age spectrum and the proportion of susceptibility that is attributable to the effects of biologic factors, HIV, and cART on iron; 2) Identify novel iron-dependent pathways, iron-metabolic genes, and iron-quantitative trait loci associated with depression and NCI in women and men with HIV, and determine the extent to which these genetic effects are mediated via iron; 3) Explore the functional impact of network-prioritized iron-related gene knockdown on production of KP metabolites, using an in vitro HIV(+/-) human microglia model. In addition, Aim 1 will associate iron indices in a subset of individuals to CSF mono-amine metabolites. We expect these studies to advance understanding of mechanisms leading to depression and NCI in people with HIV, suggesting novel precision- medicine approaches to disease management and potentially impactful, iron- or KP-modulating interventions.