Repunte-Canonigo Vez, Lefebvre Celine, George Olivier, Kawamura Tomoya, Morales Marisela, Koob George F, Califano Andrea, Masliah Eliezer, Sanna Pietro Paolo
Molecular and Cellular Neuroscience Department, La Jolla, CA 92037, USA.
Mol Neurodegener. 2014 Jul 1;9:26. doi: 10.1186/1750-1326-9-26.
A thorough investigation of the neurobiology of HIV-induced neuronal dysfunction and its evolving phenotype in the setting of viral suppression has been limited by the lack of validated small animal models to probe the effects of concomitant low level expression of multiple HIV-1 products in disease-relevant cells in the CNS.
We report the results of gene expression profiling of the hippocampus of HIV-1 Tg rats, a rodent model of HIV infection in which multiple HIV-1 proteins are expressed under the control of the viral LTR promoter in disease-relevant cells including microglia and astrocytes. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analysis. Gene expression changes observed are consistent with astrogliosis and microgliosis and include evidence of inflammation and cell proliferation. Among the genes with increased expression in HIV-1 Tg rats was the interferon stimulated gene 15 (ISG-15), which was previously shown to be increased in the cerebrospinal fluid (CSF) of HIV patients and to correlate with neuropsychological impairment and neuropathology, and prostaglandin D2 (PGD2) synthase (Ptgds), which has been associated with immune activation and the induction of astrogliosis and microgliosis. GSEA-based pathway analysis highlighted a broad dysregulation of genes involved in neuronal trophism and neurodegenerative disorders. Among the latter are genesets associated with Huntington's disease, Parkinson's disease, mitochondrial, peroxisome function, and synaptic trophism and plasticity, such as IGF, ErbB and netrin signaling and the PI3K signal transduction pathway, a mediator of neural plasticity and of a vast array of trophic signals. Additionally, gene expression analyses also show altered lipid metabolism and peroxisomes dysfunction. Supporting the functional significance of these gene expression alterations, HIV-1 Tg rats showed working memory impairments in spontaneous alternation behavior in the T-Maze, a paradigm sensitive to prefrontal cortex and hippocampal function.
Altogether, differentially regulated genes and pathway analysis identify specific pathways that can be targeted therapeutically to increase trophic support, e.g. IGF, ErbB and netrin signaling, and reduce neuroinflammation, e.g. PGD2 synthesis, which may be beneficial in the treatment of chronic forms of HIV-associated neurocognitive disorders in the setting of viral suppression.
由于缺乏经过验证的小动物模型来探究中枢神经系统中与疾病相关的细胞内多种HIV-1产物低水平表达的影响，对HIV诱导的神经元功能障碍及其在病毒抑制情况下不断演变的表型的神经生物学进行全面研究受到了限制。
我们报告了HIV-1转基因大鼠海马体的基因表达谱分析结果，HIV-1转基因大鼠是一种HIV感染的啮齿动物模型，其中多种HIV-1蛋白在病毒LTR启动子的控制下在包括小胶质细胞和星形胶质细胞在内的与疾病相关的细胞中表达。基因集富集分析（GSEA）算法用于通路分析。观察到的基因表达变化与星形胶质细胞增生和小胶质细胞增生一致，包括炎症和细胞增殖的证据。在HIV-1转基因大鼠中表达增加的基因包括干扰素刺激基因15（ISG-15），该基因先前在HIV患者的脑脊液（CSF）中显示增加，并与神经心理损害和神经病理学相关；还有前列腺素D2（PGD2）合酶（Ptgds），其与免疫激活以及星形胶质细胞增生和小胶质细胞增生的诱导有关。基于GSEA的通路分析突出了参与神经元营养和神经退行性疾病的基因的广泛失调。后者包括与亨廷顿舞蹈病、帕金森病、线粒体、过氧化物酶体功能以及突触营养和可塑性相关的基因集，如IGF、ErbB和netrin信号通路以及PI3K信号转导通路，PI3K信号转导通路是神经可塑性和大量营养信号的介质。此外，基因表达分析还显示脂质代谢改变和过氧化物酶体功能障碍。支持这些基因表达改变的功能意义的是，HIV-1转基因大鼠在T迷宫的自发交替行为中表现出工作记忆受损，T迷宫范式对前额叶皮质和海马体功能敏感。
总之，差异调节基因和通路分析确定了可以通过治疗靶向增加营养支持（例如IGF、ErbB和netrin信号通路）和减少神经炎症（例如PGD2合成）的特定通路，这可能有利于在病毒抑制情况下治疗慢性形式的HIV相关神经认知障碍。
