期刊
DISEASE MODELS & MECHANISMS
卷 10, 期 12, 页码 1489-1502出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.031773
关键词
Humanized mice; Hematopoietic stem progenitor cells; Neuronal progenitors; Astrocytes; HIV-1
资金
- National Institutes of Health [028555]
- National Institute of Neurological Disorders and Stroke [36126]
- National Institute on Aging [043540]
- NIH Office of the Director [018546]
- National Institute of General Medical Sciences [103427]
- National Cancer Institute [036727]
- National Institute of Mental Health [64570]
Studies of innate glial cell responses for progressive human immunodeficiency virus type one (HIV-1) infection are limited by a dearth of human disease-relevant small-animal models. To overcome this obstacle, newborn NOD/SCID/IL2R gamma c(-/-) (NSG) mice were reconstituted with a humanized brain and immune system. NSG animals of both sexes were transplanted with human neuroglial progenitor cells (NPCs) and hematopoietic stem cells. Intraventricular injection of NPCs symmetrically repopulated the mouse brain parenchyma with human astrocytes and oligodendrocytes. Human glia were in periventricular areas, white matter tracts, the olfactory bulb and the brain stem. HIV-1 infection led to meningeal and perivascular human leukocyte infiltration into the brain. Species-specific viral-neuroimmune interactionswere identified by deepRNA sequencing. In the corpus callosum and hippocampus of infected animals, overlapping human-specific transcriptional alterations for interferon type 1 and 2 signaling pathways (STAT1, STAT2, IRF9, ISG15, IFI6) and a range of host antiviral responses (MX1, OAS1, RSAD2, BST2, SAMHD1) were observed. Glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAG, ZNF488) were downregulated. The data sets were confirmed by real-time PCR. These viral defense-signaling patterns paralleled neuroimmune communication networks seen in HIV-1-infected human brains. In this manner, this new mousemodel of neuroAIDS can facilitate diagnostic, therapeutic and viral eradication strategies for an infected nervous system.
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