Loss of neuronal integrity during progressive HIV-1 infection of humanized mice.
Loss of neuronal integrity during progressive HIV-1 infection of humanized mice.
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DOI：
10.1523/jneurosci.5473-10.2011
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发表时间：
2011-03-02
期刊：
影响因子：
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通讯作者：
Poluektova LY
中科院分区：
文献类型：
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作者：
Dash PK;Gorantla S;Gendelman HE;Knibbe J;Casale GP;Makarov E;Epstein AA;Gelbard HA;Boska MD;Poluektova LY
在出生时将人CD34阳性的造血干细胞移植到人源化NOD/SCID-IL-2Rgc缺失小鼠中，研究了持续感染HIV-1对神经元的损伤。感染了5个月大的小鼠，并跟踪了长达15周的时间，保持了显著的血浆病毒载量，并显示出CD4+T细胞数量减少。预期的系列质子磁共振波谱测试显示，感染动物的皮质N-乙酰天冬氨酸选择性减少。弥散张量成像显示皮质灰质结构改变。死后对神经元和神经胶质标记的免疫荧光脑组织检查，通过多光谱成像显微镜捕捉并通过形态测量和荧光发射进行量化，显示神经元胞体和突触结构区域性减少。微管相关蛋白2、突触素和神经丝抗原的丢失证明了这一点。据我们所知，这项研究是第一次证明人源化小鼠感染HIV-1后失去了神经元的完整性。因此，该模型允许研究正在进行的病毒复制和病毒相关的神经变性之间的关系。
Neuronal damage induced by ongoing HIV-1 infection was investigated in humanized NOD/scid-IL-2Rgcnull mice transplanted at birth with human CD34-positive hematopoietic stem cells. Mice infected at 5 months of age and followed for up to 15 weeks maintained significant plasma viral loads and showed reduced numbers of CD4+ T cells. Prospective serial proton magnetic resonance spectroscopy tests showed selective reductions in cortical N-acetyl aspartate in infected animals. Diffusion tensor imaging revealed structural changes in cortical gray matter. Postmortem immunofluorescence brain tissue examinations for neuronal and glial markers, captured by multispectral imaging microscopy and quantified by morphometric and fluorescence emission, showed regional reduction of neuronal soma and synaptic architectures. This was evidenced by loss of microtubule-associated protein 2, synaptophysin and neurofilament antigens. This study is the first, to our knowledge, demonstrating lost neuronal integrity following HIV-1 infection in humanized mice. As such, the model permits studies of the relationships between ongoing viral replication and virus-associated neurodegeneration.