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首页> 外文期刊>BMC Medical Genomics >Systems analysis of human brain gene expression: mechanisms for HIV-associated neurocognitive impairment and common pathways with Alzheimer’s disease
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Systems analysis of human brain gene expression: mechanisms for HIV-associated neurocognitive impairment and common pathways with Alzheimer’s disease

机译：人脑基因表达的系统分析：艾滋病毒相关神经认知障碍的机制和阿尔茨海默氏病的常见途径

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Background Human Immunodeficiency Virus-1 (HIV) infection frequently results in neurocognitive impairment. While the cause remains unclear, recent gene expression studies have identified genes whose transcription is dysregulated in individuals with HIV-association neurocognitive disorder (HAND). However, the methods for interpretation of such data have lagged behind the technical advances allowing the decoding genetic material. Here, we employ systems biology methods novel to the field of NeuroAIDS to further interrogate extant transcriptome data derived from brains of HIV?+?patients in order to further elucidate the neuropathogenesis of HAND. Additionally, we compare these data to those derived from brains of individuals with Alzheimer’s disease (AD) in order to identify common pathways of neuropathogenesis. Methods In Study 1, using data from three brain regions in 6 HIV-seronegative and 15 HIV?+?cases, we first employed weighted gene co-expression network analysis (WGCNA) to further explore transcriptome networks specific to HAND with HIV-encephalitis (HIVE) and HAND without HIVE. We then used a symptomatic approach, employing standard expression analysis and WGCNA to identify networks associated with neurocognitive impairment (NCI), regardless of HIVE or HAND diagnosis. Finally, we examined the association between the CNS penetration effectiveness (CPE) of antiretroviral regimens and brain transcriptome. In Study 2, we identified common gene networks associated with NCI in both HIV and AD by correlating gene expression with pre-mortem neurocognitive functioning. Results Study 1: WGCNA largely corroborated findings from standard differential gene expression analyses, but also identified possible meta-networks composed of multiple gene ontology categories and oligodendrocyte dysfunction. Differential expression analysis identified hub genes highly correlated with NCI, including genes implicated in gliosis, inflammation, and dopaminergic tone. Enrichment analysis identified gene ontology categories that varied across the three brain regions, the most notable being downregulation of genes involved in mitochondrial functioning. Finally, WGCNA identified dysregulated networks associated with NCI, including oligodendrocyte and mitochondrial functioning. Study 2: Common gene networks dysregulated in relation to NCI in AD and HIV included mitochondrial genes, whereas upregulation of various cancer-related genes was found. Conclusions While under-powered, this study identified possible biologically-relevant networks correlated with NCI in HIV, and common networks shared with AD, opening new avenues for inquiry in the investigation of HAND neuropathogenesis. These results suggest that further interrogation of existing transcriptome data using systems biology methods can yield important information.
机译：背景技术人类免疫缺陷病毒1（HIV）感染经常导致神经认知障碍。尽管病因尚不清楚，但最近的基因表达研究已经鉴定出在患有HIV关联神经认知障碍（HAND）的个体中其转录失调的基因。但是，用于解释此类数据的方法落后于允许解码遗传材料的技术进步。在这里，我们采用NeuroAIDS领域新颖的系统生物学方法来进一步询问来自HIV + +患者大脑的现存转录组数据，以进一步阐明HAND的神经发病机理。此外，我们将这些数据与阿尔茨海默氏病（AD）个体大脑的数据进行了比较，以确定神经发病的常见途径。方法在研究1中，我们使用来自6个HIV血清阴性和15个HIV阳性病例的三个大脑区域的数据，首先采用加权基因共表达网络分析（WGCNA）来进一步探索HAND与HIV脑炎相关的转录组网络（ HIVE）和没有HIVE的HAND。然后，我们采用对症方法，采用标准表达分析和WGCNA来识别与神经认知障碍（NCI）相关的网络，而与HIVE或HAND诊断无关。最后，我们检查了抗逆转录病毒疗法的中枢神经系统渗透效力（CPE）与脑转录组之间的关联。在研究2中，我们通过将基因表达与验前神经认知功能相关联，鉴定了HIV和AD中与NCI相关的常见基因网络。结果研究1：WGCNA在很大程度上证实了标准差异基因表达分析的结果，但也确定了可能的由多个基因本体论类别和少突胶质细胞功能障碍组成的元网络。差异表达分析确定了与NCI高度相关的中枢基因，包括与神经胶质增生，炎症和多巴胺能音有关的基因。富集分析确定了在三个大脑区域中变化的基因本体论类别，最值得注意的是与线粒体功能有关的基因的下调。最后，WGCNA确定了与NCI相关的失调的网络，包括少突胶质细胞和线粒体功能。研究2：AD和HIV中与NCI相关的失调的常见基因网络包括线粒体基因，而各种癌症相关基因却被上调。结论在动力不足的情况下，本研究发现了可能与HIV中的NCI相关的生物学相关网络，以及与AD共享的常见网络，从而为调查HAND神经病学的研究开辟了新的途径。这些结果表明，使用系统生物学方法进一步审视现有转录组数据可以产生重要信息。

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