Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice.
Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice.
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DOI：
10.1186/1750-1326-9-58
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发表时间：
2014-12-18
影响因子：
15.1
通讯作者：
Gorantla S
中科院分区：
文献类型：
--
作者：
Boska MD;Dash PK;Knibbe J;Epstein AA;Akhter SP;Fields N;High R;Makarov E;Bonasera S;Gelbard HA;Poluektova LY;Gendelman HE;Gorantla S
人类免疫缺陷病毒(HIV)的宿主物种特异性限制了对人类和非人类灵长类动物的病理生物学、诊断和治疗研究。人源化小鼠作为神经系统病毒感染的模型的出现，克服了这些限制，使艾滋病毒相关终末器官疾病的研究成为可能，包括反映神经艾滋病的行为、认知和神经病理缺陷。人CD34+造血干细胞(CD34-NSG)移植的NOD/SCID-IL-2Rgc缺陷型小鼠慢性HIV-1感染可导致持续性病毒血症、严重的CD4+T淋巴细胞丢失和脑膜及血管周围的人单核巨噬细胞感染。小鼠细胞不会感染病毒。从病毒感染后8周开始，测量小鼠行为的变化。这些代谢产物包括N-乙酰天冬氨酸(NAA)、肌酸和胆碱。弥散张量磁共振成像(DTI)对照多光谱免疫组织化学染色检测神经元标记物，包括微管相关蛋白2(MAP2)、神经丝(NF)和突触素(SYN)，星形胶质细胞胶质纤维酸性蛋白(GFAP)和小胶质细胞离子钙结合适配器分子1(Iba-1)。检测髓鞘相关糖蛋白(MAG)和髓鞘少突胶质细胞糖蛋白(MOG)抗原的数量和完整性。在感染HIV-1的小鼠中很容易观察到行为异常。纵向野外活动测试表明，与未感染的对照组相比，感染HIV-1的小鼠缺乏习惯化，可能会出现记忆力丧失和持续焦虑。随着MAG的降低，大脑皮层终点NAA和肌酸水平升高。NAA和谷氨酸随着SYN和MAG的降低而降低。强烈的炎症反应反映了GFAP和IBA-1的染色强度。DTI指标与解除对胡须桶中的NF、Iba-1、MOG和MAG水平的调控，以及对胼胝体中的MAP2、NF、MAG、MOG和SYN的调控相协调。这一发现与人类HIV-1神经系统感染的一些临床、生化和病理生物学特征一致。该模型将被证明对研究HIV-1诱导的神经病理机制以及开发新的生物标记物和疾病治疗策略是有用的。本文的在线版本(DOI：10.1186/17501326-9-58)包含补充材料，授权用户可以使用。
Host-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rgcnull mice transplanted with human CD34+ hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus. Changes in mouse behavior were measured, starting at 8 weeks after viral infection. These were recorded coordinate with magnetic resonance spectroscopy metabolites including N-acetylaspartate (NAA), creatine and choline. Diffusion tensor magnetic resonance imaging (DTI) was recorded against multispectral immunohistochemical staining for neuronal markers that included microtubule associated protein-2 (MAP2), neurofilament (NF) and synaptophysin (SYN); for astrocyte glial fibrillary acidic protein (GFAP); and for microglial ionized calcium binding adaptor molecule 1 (Iba-1). Oligodendrocyte numbers and integrity were measured for myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) antigens. Behavioral abnormalities were readily observed in HIV-1 infected mice. Longitudinal open field activity tests demonstrated lack of habituation indicating potential for memory loss and persistent anxiety in HIV-1 infected mice compared to uninfected controls. End-point NAA and creatine in the cerebral cortex increased with decreased MAG. NAA and glutamate decreased with decreased SYN and MAG. Robust inflammation reflected GFAP and Iba-1 staining intensities. DTI metrics were coordinate with deregulation of NF, Iba-1, MOG and MAG levels in the whisker barrel and MAP2, NF, MAG, MOG and SYN in the corpus callosum. The findings are consistent with some of the clinical, biochemical and pathobiologic features of human HIV-1 nervous system infections. This model will prove useful towards investigating the mechanisms of HIV-1 induced neuropathology and in developing novel biomarkers and therapeutic strategies for disease. The online version of this article (doi:10.1186/1750-1326-9-58) contains supplementary material, which is available to authorized users.
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DOI：
10.1523/jneurosci.5473-10.2011
发表时间：
2011-03-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Dash PK;Gorantla S;Gendelman HE;Knibbe J;Casale GP;Makarov E;Epstein AA;Gelbard HA;Boska MD;Poluektova LY
通讯作者：
Poluektova LY
DOI：
10.1097/qad.0b013e328357f5ad
发表时间：
2012-11-13
期刊：
AIDS (London, England)
影响因子：
--
作者：
Dash PK;Gendelman HE;Roy U;Balkundi S;Alnouti Y;Mosley RL;Gelbard HA;McMillan J;Gorantla S;Poluektova LY
通讯作者：
Poluektova LY
DOI：
10.1006/jmrb.1994.1037
发表时间：
1994-03-01
期刊：
JOURNAL OF MAGNETIC RESONANCE SERIES B
影响因子：
--
作者：
BASSER, PJ;MATTIELLO, J;LEBIHAN, D
通讯作者：
LEBIHAN, D
DOI：
10.1080/09540121.2013.819401
发表时间：
2014-02-01
影响因子：
1.7
作者：
Barber, T. J.;Bradshaw, D.;Catalan, J.
通讯作者：
Catalan, J.
人类免疫缺陷病毒对重组刺激因子1处理的单核细胞的有效分离和传播。
影响因子：
15.3
作者：
GENDELMAN, HE;ORENSTEIN, JM;MARTIN, MA;FERRUA, C;MITRA, R;PHIPPS, T;WAHL, LA;LANE, HC;FAUCI, AS;BURKE, DS;SKILLMAN, D;MELTZER, MS
通讯作者：
MELTZER, MS