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

摘要 艾滋病毒携带者抑郁和神经认知障碍(NCI)的患病率要高得多。 这些疾病经常并存，降低了服药依从性和质量 寿命延长，死亡率增加至少两倍。对大量女性和男性的研究迫在眉睫 需要阐明这些疾病背后的神经生物学机制以及最近确定的性别 脆弱性方面的差异。犬尿氨酸通路中小胶质细胞介导的神经炎症和改变 (Kp)，对维持平衡的单胺类神经递质(如多巴胺和5-羟色胺)至关重要 大脑中的合成，都与这两种疾病有关。铁，受艾滋病毒和联合抗逆转录病毒的调节失调 治疗(CART)与小胶质细胞活化、KP和神经递质代谢密切相关。我们的 在单个神经HIV队列和HIV(-)人群中的初步研究表明，调控失调的重要作用 抑郁症和NCI中的铁代谢和铁相关基因网络，以及性别特异性的影响。这个 拟议的研究利用了现有的临床、铁生物标记物和全基因组数据集，这些数据集来自三个 前瞻性艾滋病毒队列研究，以有力地和全面地询问铁在抑郁症和 男性和女性都有NCI。全基因组以铁为中心的血清和脑脊液(CSF)生物标志物的组合 将采用协会、网络生物信息学等方法。这项提议的核心假设是 铁调节失调和铁相关基因/网络是导致PWH患者抑郁和NCI的主要因素， 总体风险的变异性部分可以通过年龄、性别、艾滋病毒和购物车对铁的影响来解释。具体目标是： 1)跨年龄谱确定铁稳态改变在抑郁症和NCI中在PWH中的作用 可归因于生物因素、艾滋病毒和CART对铁的影响的易感性比例；2) 确定新的铁依赖途径、铁代谢基因和铁数量性状基因 女性和男性HIV携带者的抑郁和NCI，并确定这些遗传影响的程度 通过铁介导；3)探讨网络优先铁相关基因敲除对细胞功能的影响 使用体外HIV(+/-)人小胶质细胞模型产生KP代谢物。此外，Aim 1将关联 一组个体的铁指数与脑脊液单胺代谢产物有关。我们预计这些研究将会取得进展 对导致HIV感染者抑郁和NCI的机制的理解，表明了新的精确度- 疾病管理的医学方法以及可能产生影响的铁或硫酸盐酸盐调节干预措施。

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.