Affiliation:
1. Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
Abstract
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/IL2Rγc−/− (NSG) mice were reconstituted with a humanized brain and immune systems. NSG animals of both sexes were transplanted with human neuroglial progenitors (NPC) and hematopoietic stem cells. Intraventricular injection of NPC 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 brain. Species-specific viral-neuroimmune interactions were identified by deep RNA sequencing. In the corpus callosum and hippocampus overlapping human-specific transcriptional alterations for interferon type 1 and 2 signaling pathways (STAT1, 2, IRF9, ISG15, IFI6) and a range of host antiviral responses (MX1, OAS1, RSAD2, BST2, SAMHD1) were seen in infected animals. Glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAG and 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, new mouse model of neuroAIDS can facilitate diagnostic, therapeutic and viral eradication strategies for an infected nervous system.
Funder
National Institutes of Health
National Institute of Neurological Disorders and Stroke
National Institute of Mental Health
National Institute on Aging
NIH Office of the Director
National Institute of General Medical Sciences
National Cancer Institute
Publisher
The Company of Biologists
Subject
General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)
Cited by
17 articles.
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