TY - JOUR
T1 - Systemic HIV-1 infection produces a unique glial footprint in humanized mouse brains
AU - Li, Weizhe
AU - Gorantla, Santhi
AU - Gendelman, Howard E.
AU - Poluektova, Larisa Y.
N1 - Funding Information:
This work was supported by the National Institutes of Health (028555), the National Institute of Neurological Disorders and Stroke (36126), the National Institute of Mental Health (64570), the National Institute on Aging (043540), the NIH Office of the Director (018546), the National Institute of General Medical Sciences (103427), and the National Cancer Institute (036727).
Publisher Copyright:
© 2017. Published by The Company of Biologists Ltd.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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 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 viralneuroimmune 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.
AB - 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 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 viralneuroimmune 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.
KW - Astrocytes
KW - HIV-1
KW - Hematopoietic stem progenitor cells
KW - Humanized mice
KW - Neuronal progenitors
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U2 - 10.1242/dmm.031773
DO - 10.1242/dmm.031773
M3 - Article
C2 - 29084769
AN - SCOPUS:85039767989
VL - 10
SP - 1489
EP - 1502
JO - DMM Disease Models and Mechanisms
JF - DMM Disease Models and Mechanisms
SN - 1754-8403
IS - 12
ER -