Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice

作者：Boska Michael D; Dash Prasanta K; Knibbe Jaclyn; Epstein Adrian A; Akhter Sidra P; Fields Natasha; High Robin; Makarov Edward; Bonasera Stephen; Gelbard Harris A; Poluektova Larisa Y; Gendelman Howard E^*; Gorantla Santhi

来源：Molecular Neurodegeneration, 2014, 9(1): 58.

DOI：10.1186/1750-1326-9-58

• H-1 magnetic resonance spectroscopy
• Behavioral and cognitive deficits
• Diffusion tensor imaging
• HIV-1
• Humanized mice

Background: 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-2Rg(c)(null) 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. %26lt;br%26gt;Methods: 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. %26lt;br%26gt;Results: 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. %26lt;br%26gt;Conclusions: 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.

• 出版日期2014-12-18