TY - JOUR
T1 - Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice
AU - Boska, Michael D.
AU - Dash, Prasanta K.
AU - Knibbe, Jaclyn
AU - Epstein, Adrian A.
AU - Akhter, Sidra P.
AU - Fields, Natasha
AU - High, Robin
AU - Makarov, Edward
AU - Bonasera, Stephen J
AU - Gelbard, Harris A.
AU - Poluektova, Larisa Y
AU - Gendelman, Howard Eliot
AU - Gorantla, Santhi
N1 - Funding Information:
NOD/scid-IL-2Rgcnull (NSG) mice obtained from Jackson Laboratories established breeding colonies (stock number 005557) and housed under pathogen-free conditions; done in approval and in accordance with ethical guidelines for care of laboratory animals as set forth by National Institute of Health and the University of Nebraska Medical Center (UNMC IACUC 06-071-02FC). Human CD34+ hematopoietic stem cells (HSC) were obtained from fetal liver (University of Washington, Laboratory of Developmental Biology, supported by NIH award 5R24HD000836) by magnetic bead selection (Miltenyi Biotech Inc., Auburn, CA), and NSG mice were humanized as described previously [20]. Human immune system engraftment was determined by flow cytometry in rodent peripheral blood using antibodies to human pan-CD45, CD3, CD4, CD8, CD14 and CD19 in a six-color combination (BD Pharmin-gen, San Diego, CA). The percentages of CD4+ and CD8+ T-lymphocytes were obtained from the gate set on human CD3+ cells. Humanized CD34-NSG mice were infected intraperitoneally with HIV-1ADA, a CCR5 utilizing virus at a dosage of 104 tissue culture infective dose 50 (TCID50)/ mouse at 22 weeks of age. The levels of viral replication were monitored and analyzed from plasma at defined time points by an automated COBAS Amplicor System V1.5 (Roche Molecular Diagnostics) and expressed as copies of viral RNA per ml sample (Viral load, VL) as previously
Funding Information:
The MRUI software package was kindly provided by the participants of the EU Network programmes: Human Capital and Mobility, CHRX-CT94-0432 and Training and Mobility of Researchers, ERB-FMRX-CT970160. This work was supported by the University of Nebraska Foundation which includes individual donations from Dr. Carol Swarts and Frances and Louie Blumkin, the Vice Chancellor’s office of the University of Nebraska Medical Center, ViiV Healthcare and National Institutes of Health grants P01 MH64570, RO1 MH104147, P01 DA028555, R01 NS36126, P01 NS31492, 2R01 NS034239, P01 NS43985, P30 MH062261, R01 AG043540 and a grant from the Nebraska Research Initiative.
PY - 2014
Y1 - 2014
N2 - 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-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.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.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.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.
AB - 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-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.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.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.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.
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U2 - 10.1186/1750-1326-9-58
DO - 10.1186/1750-1326-9-58
M3 - Article
C2 - 25523827
AN - SCOPUS:84939795719
SN - 1750-1326
VL - 9
SP - 58
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
ER -